Fusion proteins for the diagnosis, prophylaxis and treatment of infectious diseases

ABSTRACT

The present invention inter alia relates to the use of phosphotidylserine or pathogenic sugar targeted therapeutics for the management and treatment of microbial infections, including Zika, Dengue, West Nile, Ebola, H1N1, enteroviruses, Leishmaniasis, Malaria and Coronaviruses SARS-COV. In an aspect, the invention concerns a fusion construct comprising an Ig-Fc domain or other protein scaffold, such as albumin, and a peptide, protein, or antibody fragment binding to phosphatidylserine and/or a peptide or protein binding to and/or recognizing a PAMP expressed by a microbe. Other aspects are described.

The present specification comprises a sequence listing in computerreadable format, submitted together with the application. The sequencelisting forms part of the disclosure and is incorporated in thespecification in its entirety.

The present invention relates to the use of phosphotidylserine orpathogenic sugar targeted therapeutics for the management and treatmentof microbial infections, including Zika, Dengue, Respiratory SyncytialVirus, West Nile, Ebola, H1N1, Mycobacterium Leprae, Mycobacteriumtuberculosis, Enteroviruses, Leishmaniasis, Malaria and CoronavirusesSARS-CoV.

Provided are compositions related to novel, therapeutic proteinsincluding pathogen neutralizing proteins that may be conjugated to furinprotease inhibitors, T cell engagers, platforms with cytotoxicfunctions, mono and multivalent molecules, drug conjugates andadjuvants, carriers and methods of administration, in particularsubcutaneous, oral or nasal administration. This invention furtherrelates to a companion diagnostic as a method of selection of subjectsthat may benefit from such therapies and a blood biomarker for rapid andeasy monitoring of response of treatment.

TECHNICAL BACKGROUND

According to WHO, the Arborviruses Zika Virus (ZIKV), Chikungunya(CHIKV), Dengue (DENV), West Nile (WNV), as well as Ebola (EBLV) andSARS are relatively recent, life-threatening, rare diseases prone topandemic spread that pose a high global public health risk (WHO report2020).

There are no FDA approved therapies for these diseases. A live,recombinant vaccine consisting of the envelope glycoprotein of one ofthe Ebola strains, Zaire Ebolavirus (Ervebo, 2019) was recently approvedby the FDA for adult use only, although the duration of protection isstill not entirely known. Another recombinant vaccine consisting of thepre-M and E proteins for all 4 strains of Dengue (Dengvaxia, 2019) hasalso been approved however Lim et al 2019 reported new mutations in DENVwith different antigenic properties.

ZIKV, WNV and DENV are flaviviruses (family Flaviviridae) primarilytransmitted by mosquito vectors (i.e. arboviruses). Zika is a positivesingle stranded RNA flaviviridae virus mainly transmitted by the Aedesmosquito and an increasing number of strains in two phylogeneticlineages (Asian and African) have been identified since its firstisolation in Uganda in 1947 (Ramos da Silva 2016). According to WHOoutbreaks in 2015-2017 resulted in more than 30,000 cases worldwide(Worlds Health Organization Zika Epidemiology update July 2019, Website:www_who.int/emergencies/diseases/zika/zika-epidemiology-update-july-2019.pdf?ua=1,accessed 5 Aug. 2020).

According to Musso 2015, Zika is also spread through sexual contact(Musso 2015) and according to Rasmussen 2016, Zika is also spread frommaternal to fetal blood (Rasmussen 2016).

An expanding spectrum of neurological sequelae has been reported.According to Rasmussen 2016 a particularly serious co-morbidity of Zikainfection in pregnant women is severe congenital microcephaly to theirprogeny (Rasmussen 2016). According to Barbi 2018, in adults,Guillain-Barré syndrome (GBS), an auto-immune disease that destroys themyelin sheath and causes progressive ascending paralysis has beenestimated to affect 1.23% of patients (Barbi 2018). Other reported ZIKVneurological complications include encephalitis/meningoencephalitis,acute disseminated encephalomyelitis, myelitis, cerebrovascularcomplications, seizures and encephalopathy, sensory polyneuropathy andsensory neuropathy.

Primary hosts of ZIKV include human, monkey, and mosquito. According toHou 2017 neural stem cells, fibroblasts, epithelial and blood cells arepermissive to ZIKV infection (Hou 2017).

Dengue virus (DEGV) is a negative RNA strand flavivirus that causes themost prevalent arthropod-born viral disease in the world (1 millioncases/year). DENV infection causes human diseases with a wide spectrumof clinical symptoms, ranging from asymptomatic infection orself-limited febrile illness named Dengue fever (DF) to life-threateningdiseases including Dengue hemorrhagic fever (DHF) and Dengue shocksyndrome (DSS). There are currently no therapies for Dengue nor avaccine for individuals not previously infected by Dengue or travellingfrom non-endemic areas. Dengvaxia is a vaccine approved for individuals9 through 16 years of age with laboratory-confirmed previous dengueinfection and living in endemic areas.

The Pat. Application US2009175865A1 describes antibodies that areengineered by replacing one or more amino acids of a parent antibodywith non-cross-linked, highly reactive cysteine amino acids. Among othermutations, the patent application mentions A339C and S337C.

The patent application WO2015157595 describes conjugate compoundscomprising antibodies and fragments thereof engineered with one or morereactive cysteine residues. Among other mutations, the patentapplication mentions K340C.

According to Wenwen Bi et al. (IgG Fc-binding mortif-conjugated HIV-1fusion inhibitor exhibits improved potency and in vivo half-life:Potential application in combination with broad neutralizing antibodies,PLOS Pathogens, Dec. 5, 2019.) a strategy have been developed to extendthe in vivo half-life of a short HIV-1 fusion inhibitory peptide, CP24,by fusing it with the human IgG Fc-binding peptide (IBP).

SUMMARY OF THE INVENTION

There is an unmet need for new technologies to manage emerging as wellas re-emerging infectious diseases prone to genetic variability.

Similarities in the way viruses bind to permissive human cells, areactivated in the endosomal-lysosomal compartments and become infectious,offer insights towards a potential pan-therapeutic approach to theirtreatment.

Pathogen Sugars as a Cd209 Therapeutic Target

Glycans are essential structural and functional components of microbes.Among these, glucans, polysaccharide moieties derived from D-glucose,are prominent constituents of the cell walls of fungi, plants, andmycobacteria. High mannose containing structures (mannans) are expressedby many viruses, fungi, and bacteria, and fucose structures (fucans) arefound on the surface of helminths and some bacteria (Geijtenbeek andGringhuis, 2009; Robinson et al., 2006).

The human immune system has evolved innate pattern-recognition receptorsthat discern self from non-self-glycans. Binding of C-type lectins topathogen sugars triggers both innate and adaptive immune events thatlead to pathogen clearance however this interaction may also beexploited to enhance pathogenicity.

The myeloid, dendritic and macrophage cell specific C-type lectinreceptor CD209 (also known as DC-SIGN), (Zelensky and Gready, 2005) isan important host cell receptor for entry of ZIKV (Perera Lecoin, 2013,Osorio and Sousa 2011), Influenza (Gillespie 2016), DENV (Cruz-Oliveira,2015), WNV (Davis 2006), Ebola (Alvarez 2002), enterovirus (REN 2014),mycobacterium tuberculosis (Tailleux 2003) and mycobacterium Leprae(Barreiro 2006) and SARS-COV2/COVID19 (Amraei 2020, Cai 2020, Jeffers2004). The protozoan vector borne disease Leshmaniasis and Malaria arenon-viral pathogens that may exploit CD209 for host entry (Colmenares2002, Morenikeji 2020). CD209 binds to both mannan (high-mannoseN-linked oligosaccharides) and fucan moieties that comprise viralsignatures or “pathogen associated molecular patterns (PAMPs). Thebinding occurs within a compact protein region with a unique structuralfold that became known as the “C-type carbohydrate recognition domain”or “C-type lectin domain (CTLD)” (Weis and Drick- Amer, 1996).

There is no cure for COVID-19, currently a worldwide pandemic, howeverthe FDA has granted emergency use authorization for the antiviralRemdesivir, although their effectiveness against Covid-19 has yet to bedemonstrated in large-scale, randomized clinical trials. Amongapproaches in early preclinical development are ACE2 decoy proteins toblock viral attachment to host cells, and off-label use of dexamethasoneto reduce inflammation in patients on ventilators but not patients withearly stage symptoms. Thus, there is an urgent need for effective andsafe means for treating and alleviating COVID-19 and related symptoms.Thus, there is an urgent need for a diagnostic that can precisely selectpatients that may benefit from a particular treatment.

Phosphatidylserine (ps) Lipids as a Tim1 Therapeutic Target

The outer virus membrane layer of several viruses is rich inphospholipid phosphatidylserine (PS) whereas in the host cell membrane,PS is normally restricted to the inner membrane layer.

The T-cell immunoglobulin and mucin domain 1 (TIM-1) human membranereceptor functions as a potent co-stimulatory molecule for T-cellactivation.

TIM1 (also known as HAVCR1) is a type I transmembrane glycoprotein thatcontains an extracellular domain composed of an N-terminalimmunoglobulin variable (IgV)-like domain followed by a glycosylatedmucin domain, a single transmembrane domain, and a short cytoplasmictail with tyrosine phosphorylation motifs. The Ig V domain of TIM1 ispredicted to contain a conserved PS binding site (Santiago et al.,2007).

TIM-1 is expressed preferentially on T-helper 2 (Th2) cells in thebrain, gastrointestinal tract, liver and gallbladder, kidney, testis andlymphoid tissue. According to Freeman 2010 TIM-1 recognizes and attachesto exposed PS with high specificity in dying, apoptotic cells andtriggers their phagocytosis by the immune system (Freeman 2010). TIM-1promotes apoptotic clearance by binding to PS through its metalion-dependent ligand binding site (MILIBS) within the IgV domain.

It has also been shown that TIM1 is an entry factor for highly divergentviruses (Jemielity, 2013), including Zika (Lee 2018), Ebola (Brunton2019), Dengue (Chu 2019, Amara 2015), West Nile (Richard 2015),Hepatitis A and possibly Malaria (Nuchnoi 2020).

These studies indicate that TIM-1, functions as a common attachmentfactor for a range of enveloped viruses through direct interaction withPS of the viral envelope independent of glycoproteins.

TIM1 is the most well-known PS receptor although other PS receptors havebeen described to a lesser extent such as Tyro3, Axl and Mer of the TAMfamily of proteins.

Tim-1 as a Receptor for Viral Proteins

According to Angiari et al. 2014, TIM-1 plays a role in autoimmune andinflammatory disease development by controlling T cell adhesion throughbinding to P-selectin proteins via the TIM-1 mucin and IgV domains(Angiari 2014).

Kuroda et al. 2015 reported that filovirus infection and GP-mediatedmembrane fusion were significantly suppressed by treatment with aTIM-1-specific monoclonal antibody that interfered with the interactionbetween TIM-1 and Niemann-Pick C1 Protein (NPC1). This study suggestedthat TIM-1 may also participate in viral membrane fusion.

According to Yuan et al. 2015, human TIM-1 directly binds to EBOVglycoprotein (GP) and the authors determined the crystal structures ofthe Ig V domains of hTIM-1 and hTIM-4 as well as the binding region.

According to Kondratowicza et al. 2010, TIM-1 on host epithelial cellsof the trachea, cornea, and conjunctiva, binds directly to the receptorbinding domain of the Zaire Ebola virus (EBOV) glycoprotein and enhancesairborne and hand-to-eye infection. Blockage of this interaction withantibodies inhibited binding and Ebola infection.

Thus, TIM-1 may have both protein dependent and independent functions inviral infection.

Furin Protease Inhibition as a Therapeutic Strategy

Furin cleavage sites are present in entry proteins of Zika, Dengue,COVID-19 (Coutard 2020), Ebola, HIV, and Hepatitis B viruses amongothers (Braun 2019).

Decanoyl-Arg-Val-Lys-Arg-chloromethylketone (dec-RVKR-cmk) comprisingSEQ ID NO. 81 and hexa-D-arginine (D6R) are small synthetic furininhibitors that have been used to show reduction of viral infectivity invitro (Owczarek, 2019, Imran 2019, Remacle 2010, Couture 2015). CMK ismore effective than D6R in the reduction of Hepatitis replication byinhibiting furin-mediated processing of the hepatitis B e-antigen(HBeAg) precursor into mature HBeAg. Dec-RVKR-cmk is a small, synthetic,irreversible, and cell-permeable competitive inhibitor of all proproteinconvertases (PC1, PC2, PC4, PACE 4, PC5, PC7, and furin). CMK isreported to inhibit furin-mediated cleavage and fusion activity of viralglycoproteins, and acts as an antiviral agent against different viruses,including human immunodeficiency virus, Chikungunya virus, chronichepatitis B virus, influenza A, Ebola virus infection and papillomavirus. Smith et al. and Steinmetzer et al. also patented apeptidomimetic furin inhibitor by modifying the C-terminal ofdec-RVKR-cmk with decarboxylated arginine mimetics, resulting in highlypotent furin inhibitors (Couture 2015).

Wide-range furin/proprotein inhibitors are thought to have minimaloff-pathogen, on-target effects in the host given that proproteinconvertases are highly redundant, as shown by furin knockout mice.

CMK has been shown to have anti-flavivirus activity at non-cytotoxicconcentration (Imran 2019).

Zika virus contains 3 structural (capsid-pC, envelope-pE andmembrane-prM) and 7 non-structural (NS) proteins (NS1, NS2A, NS2B, NS3,NS4A, NS4B and NS5). Zika virus replication occurs in the permissivehost cell after internalization via clathrin-mediated pH dependentendocytosis and maturation of viral proteins in the lysosomalcompartment (Owczarek, 2019). In the lysosome, furin or furin-likeproteases cleave viral surface glycoprotein prM into its active formdestabilizing the viral membrane and promoting release of the viral RNAfor replication in mitochondria and endoplasmatic reticulum.

There is no vaccine for ZIKV although there are investigational agentsin clinical development.

It has been shown that furin inhibition causes the immature virion to betransported to late compartments where it undergoes proteolyticdegradation. The degradation products are ejected from the cell via slowrecycling vesicles (Owczarek, 2019).

Like ZIKV, DENV binding of viral protein E with cellular receptorsallows viral particles to internalize into the permissible cell via thechlathrin mediated endocytosis pathway. To release the viral RNA genome,DENV virions undergo an acid-induced conformational change and membranefusion. Newly synthesized viral proteins generated near the endoplasmicreticulum (ER) promote replication of the viral RNA genome, induction ofmembrane rearrangement, and assembly of new viral particles. Tofacilitate the process of DENV replication, DENV not only interacts withvarious cellular components, but also triggers various host responses,such as autophagy.

T-cell Mediated Therapy

CD3 is a protein complex and T cell co-receptor that is involved inactivating T cells. CD3 is selectively expressed on T cells in blood,bone marrow and lymphoid tissues, but not on other normal tissues andwith no cross reactivity to other animals except for chimpanzee.Recently, human CD3 transgenic mice have been engineered, facilitatingthe study of anti-CD3 immunotherapies.

Anti-CD3 based therapies such as muromomab-CD3 (Janssen, Orthoclone,OKT3) have been extensively studied in humans both systemically andorally to block reactive T cells and ameliorate ulcerative cholitis andmetabolic syndrome (da Cunha 2011, Ilan 2010-NCT01287195, NCT01205087).Anti-CD3 bispecific antibody platforms that bridge tumors and engage Tcells such as blinatumomab and catumaxomab have been approved for thetreatment of cancer and several others CD3 bispecifics are in clinicaldevelopment (Suurs, 2019).

According to an aspect, the invention concerns a fusion constructcomprising an Ig-Fc domain or other protein scaffold, such as albumin,and

-   a. a peptide, protein, or antibody fragment binding to    phosphatidylserine and/or-   b. a peptide or protein binding to and/or recognizing a PAMP    expressed by a microbe.

PAMP refers to Pathogen-associated molecular pattern: conservedmolecular structures produced by microbial pathogens, but not by thehost organism that are recognized by the host innate immune system.

According to another aspect, the invention concerns a fusion constructcomprising an IgG-Fc domain or other protein scaffold and

-   a. a recombinant human TIM1 fragment and/or-   b. a recombinant human CD209 fragment.

According to another aspect, the invention concerns a fusion constructcomprising an IgG-Fc domain or other protein scaffold and

-   a. a recombinant human TIM1 fragment and/or-   b. a recombinant human CD209 fragment

and wherein said fusion construct provides enhanced ADCC, ADCP and/orCDC.

ADCC may be defined as Antibody-Dependent Cellular Cytotoxicity. ADCPmay be defined as Antibody-Dependent Cellular Phagocytosis. CDC may bedefined as Complement-dependent cytotoxicity.

According to another aspect, the invention concerns a fusion constructcomprising an IgG-Fc domain or other protein scaffold and

-   a. a recombinant human TIM1 fragment and/or-   b. a recombinant human CD209 fragment

and wherein said fusion construct additionally comprises the CDR regionsaccording to SEQ ID No.: 54 - 59.

According to another aspect, the invention concerns a fusion constructcomprising an IgG-Fc domain or other protein scaffold and

-   a. a recombinant human TIM1 fragment and/or-   b. a recombinant human CD209 fragment

and wherein said fusion construct further comprises a Furin inhibitor.

Preferably the Furin inhibitor is selected among chloromethylketone andD-arginine derivatives such as hexa-D-arginine and dec-RVKR-cmk(comprising SEQ ID NO. 81).

The linker and spacers may be conjugated to furin, see Table 7.

According to another aspect, the invention concerns a fusion construct,wherein said fusion construct is an IgG3 construct, and wherein saidIgG3 construct comprises a hinge region, wherein said hinge region hasbeen modified.

According to another aspect, the invention concerns a fusion construct,a fusion protein or an antibody comprising the constant region(s) ofIgG3 and a hinge, wherein said hinge preferably is selected among anIgG1 or IgG4 hinge.

According to another aspect, the invention concerns IgG3 homodimercomprising a hinge region, wherein said hinge region comprises asequence selected among SEQ ID No.: 6, 8 and 68.

According to another aspect, the invention concerns IgG3 heterodimercomprising a hinge region, wherein said hinge region comprises asequence selected among SEQ ID No.: 6, 8 and 68.

According to another aspect, the invention concerns IgG3, wherein saidIgG3 comprises a mutation at position 405 and/or position 409. Accordingto another aspect, the invention concerns IgM heterodimers obtainable bychanging the charge pairs of the CH2 and/or CH4 domains.

According to another aspect, the invention concerns IgM heterodimers,comprising one or more of the mutations of Table 8.

According to another aspect, the invention concerns a fusion construct,wherein said fusion construct comprises an IgG3 homodimer, an IgG3heterodimer and/or an IgM heterodimer according to the invention.

According to another aspect, the invention concerns use of a fusionconstruct according to the invention for the treatment of an infection.

According to another aspect, the invention concerns use, wherein saidinfections are selected among viral, bacterial, and protozoaninfections.

According to another aspect, the invention concerns use, wherein thetreatment comprising administration of the fusion construct with anadministration form selected among subcutaneous, intradermal,intramuscular, oral and nasal.

According to another aspect, the invention concerns use of IgG4 or apart of IgG4 for payload delivery, wherein said IgG4 has been modifiedto comprise no Fc or wherein the activity of the Fc of said IgG4 hasbeen nullified or diminished by one or more mutations.

According to another aspect, the invention concerns a vaccine comprisinga fusion construct according to the invention.

According to another aspect, the invention concerns a vaccine comprisinga mannan, a high mannose containing structure, a fucan and/or aphospholipid phosphatidylserine (PS).

According to another aspect, the invention concerns a compositioncomprising a fusion construct according to the invention, optionallycomprising one or more excipients such as diluents, binders or carriers.

According to another aspect, the invention concerns a method of treatingand/or preventing an infection in a subject, comprising a step ofadministration of a fusion construct and/or a vaccine and/or acomposition according to the invention.

According to another aspect, the invention concerns a method ofscreening and/or monitoring progression of a disease in a subject,wherein said method comprises the following steps:

-   i. Providing a blood sample from said subject.-   ii. Contacting said blood sample with a fusion construct according    to the invention.

According to another aspect, the invention concerns an isolated nucleicacid molecule encoding a fusion construct according to the invention.

According to another aspect, the invention concerns a recombinant vectorcomprising the nucleic acid molecule of the invention.

According to another aspect, the invention concerns a host cellcomprising the recombinant vector of the invention.

According to another aspect, the invention concerns a method to producea fusion construct according to the invention comprising a step ofculturing the host cell according to the invention in a culture mediumunder conditions allowing the expression of the fusion construct andseparating the fusion construct from the culture medium.

DETAILED DISCLOSURE

According to an embodiment, the invention concerns a fusion constructcomprising an Ig-Fc domain or other protein scaffold, such as albumin,and

-   a. a peptide, protein, or antibody fragment binding to    phosphatidylserine and/or-   b. a peptide or protein binding to and/or recognizing a PAMP    expressed by a microbe.

PAMP refers to Pathogen-associated molecular pattern: conservedmolecular structures produced by microbial pathogens, but not by thehost organism that are recognized by the host innate immune system.

The term “protein scaffold” refers to a protein structure on which theactive elements defined in a. and b. above can be bound. The proteinscaffold should preferably be soluble in plasma and preferably have ahigh residence time in plasma, which typically can be provided if thecomplete fusion protein has a size above the renal clearance limit, suchas above 60 kDa, or by selecting a protein scaffold that is subject toan active retention system e.g. proteins binding and recycled to theplasma via the FcRn receptor. Examples of suitable protein scaffoldsinclude plasma proteins or fragments thereof, such as constant regionsof immunoglobulins, albumin, albumin domain I, II, or III, transferrinand lactoferrin.

According to an embodiment, the invention concerns a fusion constructcomprising an IgG-Fc domain or other protein scaffold and

-   a. a recombinant human TIM1 fragment and/or-   b. a recombinant human CD209 fragment.

According to an embodiment, the invention concerns a fusion constructcomprising an IgG-Fc domain or other protein scaffold and

-   a. a recombinant Ig-like V-type domain of a human TIM1 fragment    and/or-   b. a recombinant C-type lectin domain of a human CD209 fragment.

According to an embodiment, the invention concerns a fusion constructcomprising an IgG-Fc domain or other protein scaffold and

-   a. two or more recombinant Ig-like V-type domains from one or more    human TIM1 fragment(s) and/or-   b. two or more recombinant C-type lectin domains from one or more    human CD209 fragment(s).

According to an embodiment, the invention concerns a fusion constructcomprising

-   a. a recombinant Ig-like V-type domain of a human TIM1 fragment and-   b. a recombinant C-type lectin domain of a human CD209 fragment.

According to an embodiment, the invention concerns a fusion constructcomprising an IgG-Fc domain or other protein scaffold and

-   a. a recombinant human TIM1 fragment and/or-   b. a recombinant human CD209 fragment

and wherein said fusion construct provides enhanced ADCC, ADCP and/orCDC.

ADCC may be defined as Antibody-Dependent Cellular Cytotoxicity. ADCPmay be defined as Antibody-Dependent Cellular Phagocytosis. CDC may bedefined as Complement-dependent cytotoxicity.

According to an embodiment, the invention concerns a fusion constructcomprising an IgG-Fc domain or other protein scaffold and

-   a. a recombinant human TIM1 fragment and/or-   b. a recombinant human CD209 fragment

and wherein said fusion construct additionally comprises the CDR regionsaccording to SEQ ID No.: 54 - 59.

According to an embodiment, the invention concerns a fusion constructcomprising an IgG-Fc domain or other protein scaffold and

-   a. a recombinant human TIM1 fragment and/or-   b. a recombinant human CD209 fragment

and wherein said fusion construct further comprises a Furin inhibitor.

Preferably the Furin inhibitor is selected among chloromethylketone andD-arginine derivatives such as hexa-D-arginine and dec-RVKR-cmk(comprising SEQ ID NO. 81).

The linker and spacers may be conjugated to furin, see Table 7.

According to an embodiment, the invention concerns the fusion construct,wherein said peptide, protein or antibody fragment is capable of bindingto and/or stimulating an immune cell.

According to an embodiment, the invention concerns the fusion construct,wherein said TIM1 fragment has a sequence length selected from the groupconsisting of 40-200 amino acid residues, 50-180 amino acid residues,60-160 amino acid residues, 70-140 amino acid residues, 80-130 aminoacid residues, 90-120 amino acid residues, 100-120 amino acid residuesand 100-110 amino acid residues.

According to an embodiment, the invention concerns the fusion construct,wherein said CD209 fragment has a sequence length selected from thegroup consisting of 40-200 amino acid residues, 40-190 amino acidresidues, 50-180 amino acid residues, 60-170 amino acid residues, 70-160amino acid residues, 80-150 amino acid residues, 90-150 amino acidresidues, 100-150 amino acid residues, 110-150 amino acid residues,120-150 amino acid residues and 130-140 amino acid residues.

According to an embodiment, the invention concerns the fusion construct,wherein said TIM1 and/or CD209 fragment has a sequence homology of atleast 70%, alternatively 75%, alternatively 80%, alternatively 85%,alternatively 90%, alternatively 95% to wildtype TIM1 or CD209.

According to an embodiment, the invention concerns the fusion construct,wherein said TIM1 and/or CD209 fragment has intact TIM1 and/or CD209function.

According to an embodiment, the invention concerns the fusion construct,wherein said IgG-Fc domain is an IgG3-Fc domain.

According to an embodiment, the invention concerns the fusion construct,comprising additionally at least one of the following:

-   a) An IgG3, wherein the hinge sequence has been replaced, preferably    with an IgG4 hinge sequence;-   b) CDR regions according to SEQ ID No.: 54 - 59 and/or-   c) A furin inhibitor.

According to an embodiment, the invention concerns the fusion construct,wherein said fusion construct comprises a sequence according to SEQ IDNo.: 1 and/or SEQ ID No.: 2.

According to an embodiment, the invention concerns the fusion construct,wherein said fusion construct comprises a sequence according to SEQ IDNo.: 3 and/or SEQ ID No.: 4.

According to an embodiment, the invention concerns the fusion construct,wherein said fusion construct comprises at least 1, at least 2, at least3, at least 4, at least 5, at least 6, at least 7 or preferably at least8 disulfide bonds.

According to an embodiment, the invention concerns the fusion construct,wherein said fusion construct is capable of binding to a target, andwherein said target is a mannan, a high-mannose containing structure, afucan, a phospholipid phosphatidylserine and/or CD3.

According to an embodiment, the invention concerns the fusion construct,wherein said fusion construct comprises:

-   a. A protein fragment comprising or consisting of a sequence    according to SEQ ID No.: 1, or a sequence with at least 90% sequence    identity, preferably at least 95% sequence identity, more preferred    at least 98% sequence identity to this sequence, and-   b. a protein fragment comprising or consisting of a sequence    according to SEQ ID No.: 3 or a sequence with at least 90% sequence    identity, preferably at least 95% sequence identity, more preferred    at least 98% sequence identity to this sequence.

According to an embodiment, the invention concerns the fusion construct,wherein said fusion construct comprises:

-   a. A first chain comprising    -   i. a sequence according to SEQ ID No.: 1, SEQ ID No.: 2, or a        sequence with at least 90% sequence identity, preferably at        least 95% sequence identity, more preferred at least 98%        sequence identity to one of these sequences, and    -   ii. a sequence according to SEQ ID No.: 9, SEQ ID No.: 43, or a        sequence with at least 90% sequence identity, preferably at        least 95% sequence identity, more preferred at least 98%        sequence identity to one of these sequences, and-   b. A second chain comprising    -   iii. a sequence according to SEQ ID No.: 1, SEQ ID No.: 2, or a        sequence with at least 90% sequence identity, preferably at        least 95% sequence identity, more preferred at least 98%        sequence identity to one of these sequences, and    -   iv. a sequence according to SEQ ID No.: 9, SEQ ID No.: 43, or a        sequence with at least 90% sequence identity, preferably at        least 95% sequence identity, more preferred at least 98%        sequence identity to one of these sequences.

According to an embodiment, the invention concerns the fusion construct,wherein said fusion construct comprises:

-   a. A first chain comprising    -   i. a sequence according to SEQ ID No.: 3, SEQ ID No.: 4, or a        sequence with at least 90% sequence identity, preferably at        least 95% sequence identity, more preferred at least 98%        sequence identity to one of these sequences, and    -   ii. a sequence according to SEQ ID No.: 9, SEQ ID No.: 43, or a        sequence with at least 90% sequence identity, preferably at        least 95% sequence identity, more preferred at least 98%        sequence identity to one of these sequences, and-   b. A second chain comprising    -   iii. a sequence according to SEQ ID SEQ ID No.: 3, SEQ ID No.:        4, or a sequence with at least 90% sequence identity, preferably        at least 95% sequence identity, more preferred at least 98%        sequence identity to one of these sequences, and    -   iv. a sequence according to SEQ ID No.: 9, SEQ ID No.: 43, or a        sequence with at least 90% sequence identity, preferably at        least 95% sequence identity, more preferred at least 98%        sequence identity to one of these sequences.

According to an embodiment, the invention concerns the fusion construct,wherein said fusion construct comprises:

-   a. A first chain comprising    -   i. a sequence according to SEQ ID No.: 1, SEQ ID No.: 2, or a        sequence with at least 90% sequence identity, preferably at        least 95% sequence identity, more preferred at least 98%        sequence identity to one of these sequences, and    -   ii. a sequence according to SEQ ID No.: 11, SEQ ID No.: 45, or a        sequence with at least 90% sequence identity, preferably at        least 95% sequence identity, more preferred at least 98%        sequence identity to one of these sequences, and-   b. A second chain comprising    -   iii. a sequence according to SEQ ID No.: 3, SEQ ID No.: 4, or a        sequence with at least 90% sequence identity, preferably at        least 95% sequence identity, more preferred at least 98%        sequence identity to one of these sequences, and    -   iv. a sequence according to SEQ ID No.: 13, SEQ ID No.: 47, or a        sequence with at least 90% sequence identity, preferably at        least 95% sequence identity, more preferred at least 98%        sequence identity to one of these sequences.

According to an embodiment, the invention concerns the fusion construct,wherein said fusion construct comprises:

-   a. A first chain comprising    -   i. a sequence according to SEQ ID No.: 1, SEQ ID No.: 2, or a        sequence with at least 90% sequence identity, preferably at        least 95% sequence identity, more preferred at least 98%        sequence identity to one of these sequences, and    -   ii. a sequence according to SEQ ID No.: 14, 15, 66, or a        sequence with at least 90% sequence identity, preferably at        least 95% sequence identity, more preferred at least 98%        sequence identity to one of these sequences, and-   b. A second chain comprising    -   iii. a sequence according to SEQ ID No.: 1, SEQ ID No.: 2, or a        sequence with at least 90% sequence identity, preferably at        least 95% sequence identity, more preferred at least 98%        sequence identity to one of these sequences, and    -   iv. a sequence according to SEQ ID No.: 16, 17, 67, or a        sequence with at least 90% sequence identity, preferably at        least 95% sequence identity, more preferred at least 98%        sequence identity to one of these sequences, and    -   v. a linker sequence, preferably according to SEQ ID No.: 41,        and    -   vi. a sequence according to any of the sequences selected among        SEQ ID No.: 18 - 35, or a sequence with at least 90% sequence        identity, preferably at least 95% sequence identity, more        preferred at least 98% sequence identity to one of these        sequences.

According to an embodiment, the invention concerns the fusion construct,wherein said fusion construct comprises:

-   a. A first chain comprising    -   i. a sequence according to SEQ ID No.: 3, SEQ ID No.: 4, or a        sequence with at least 90% sequence identity, preferably at        least 95% sequence identity, more preferred at least 98%        sequence identity to one of these sequences, and    -   ii. a sequence according to SEQ ID No.: 14, 15, 66, or a        sequence with at least 90% sequence identity, preferably at        least 95% sequence identity, more preferred at least 98%        sequence identity to one of these sequences, and-   b. A second chain comprising    -   iii. a sequence according to SEQ ID No.: 3 and/or SEQ ID No.: 4,        or a sequence with at least 90% sequence identity, preferably at        least 95% sequence identity, more preferred at least 98%        sequence identity to one of these sequences, and    -   iv. a sequence according to SEQ ID No.: 16, 17, 67, or a        sequence with at least 90% sequence identity, preferably at        least 95% sequence identity, more preferred at least 98%        sequence identity to one of these sequences, and    -   v. a linker sequence preferably according to SEQ ID No.: 41, and    -   vi. a sequence according to any of the sequences selected among        SEQ ID No.: 18 - 35, or a sequence with at least 90% sequence        identity, preferably at least 95% sequence identity, more        preferred at least 98% sequence identity to one of these        sequences.

According to an embodiment, the invention concerns the fusion construct,wherein said fusion construct comprises:

-   a. A first chain comprising    -   i. a sequence according to SEQ ID No.: 1, SEQ ID No.: 2, or a        sequence with at least 90% sequence identity, preferably at        least 95% sequence identity, more preferred at least 98%        sequence identity to one of these sequences, and    -   ii. a sequence according to SEQ ID No.: 14, 15, 66, or a        sequence with at least 90% sequence identity, preferably at        least 95% sequence identity, more preferred at least 98%        sequence identity to one of these sequences, and-   b. A second chain comprising    -   iii. a sequence according to SEQ ID No.: 3, SEQ ID No.: 4, or a        sequence with at least 90% sequence identity, preferably at        least 95% sequence identity, more preferred at least 98%        sequence identity to one of these sequences, and    -   iv. a sequence according to SEQ ID No.: 16, 17, 67, or a        sequence with at least 90% sequence identity, preferably at        least 95% sequence identity, more preferred at least 98%        sequence identity to one of these sequences, and    -   v. a linker sequence preferably according to SEQ ID No.: 41, and    -   vi. a sequence according to any of the sequences selected among        SEQ ID No.: 18 - 35, or a sequence with at least 90% sequence        identity, preferably at least 95% sequence identity, more        preferred at least 98% sequence identity to one of these        sequences.

According to an embodiment, the invention concerns the fusion construct,wherein said fusion construct comprises

-   a. A first chain comprising    -   i. a sequence according to SEQ ID No.: 1, SEQ ID No.: 2, or a        sequence with at least 90% sequence identity, preferably at        least 95% sequence identity, more preferred at least 98%        sequence identity to one of these sequences, and    -   ii. a sequence according to SEQ ID No.: 16, 17, 67, or a        sequence with at least 90% sequence identity, preferably at        least 95% sequence identity, more preferred at least 98%        sequence identity to one of these sequences, and    -   iii. a linker sequence preferably according to SEQ ID No.: 41,        and    -   iv. a sequence according to any of the sequences selected among        SEQ ID No.: 18 - 35, or a sequence with at least 90% sequence        identity, preferably at least 95% sequence identity, more        preferred at least 98% sequence identity to one of these        sequences, and-   b. A second chain comprising    -   v. a sequence according to SEQ ID No.: 3, SEQ ID No.: 4, or a        sequence with at least 90% sequence identity, preferably at        least 95% sequence identity, more preferred at least 98%        sequence identity to one of these sequences,    -   vi. a linker sequence preferably according to SEQ ID No.: 41,        and    -   vii. a sequence according SEQ ID No.: 14, 15, 66, or a sequence        with at least 90% sequence identity, preferably at least 95%        sequence identity, more preferred at least 98% sequence identity        to one of these sequences.

According to an embodiment, the invention concerns the fusion construct,wherein said fusion construct comprises a linker.

According to an embodiment, the invention concerns the fusion construct,wherein said linker is selected among a (GGGGS)3 linker (SEQ ID NO. 41),a (GGGGS)4 linker (SEQ ID NO. 70), a (GGGGS)5 linker (SEQ ID NO. 71) anda (GGGGS)6 linker (SEQ ID NO. 72).

A (GGGGS) linker may be defined as a Gly-Gly-Gly-Gly-Ser linker (SEQ IDNO. 69).

According to an embodiment, the invention concerns the fusion construct,wherein said fusion construct comprises at least one free cysteineresidue, at least two free cysteine residues, at least three freecysteine residues, at least four free cysteine residues, at least fivefree cysteine residues or preferably at least six free cysteineresidues.

According to an embodiment, the invention concerns the fusion construct,wherein said free cysteine allows interaction with a drug and/or apayload.

According to an embodiment, the invention concerns the fusion construct,wherein said payload is a furin inhibitor.

According to an embodiment, the invention concerns the fusion construct,wherein said fusion construct comprises a A339C mutation, a S337Cmutation and/or a K340C mutation.

According to an embodiment, the invention concerns the fusion construct,wherein said fusion construct comprises a sequence selected among any ofthe sequences SEQ ID No.: 36, 37, SEQ ID No.: 38, 39, 40, 42, 44 or 46.

According to an embodiment, the invention concerns the fusion construct,wherein said fusion construct is an IgG1, IgG2, IgG3 or an IgG4.

According to an embodiment, the invention concerns the fusion construct,wherein said fusion construct is an IgG, IgM, IgA, IgD or an IgE.

According to an embodiment, the invention concerns the fusion construct,wherein said fusion construct comprises a null fc.

According to an embodiment, the invention concerns the fusion construct,wherein said null fc comprises an Ala substitution at position 234and/or Ala substitution at 235, and/or N297A, and/or a K322A mutation.

According to an embodiment, the invention concerns the fusion construct,wherein said fusion construct comprises a heterodimerization domain.

According to an embodiment, the invention concerns the fusion construct,wherein said heterodimerization domain comprises a sequence according toSEQ ID No.: 48, 49 or 50.

According to an embodiment, the invention concerns the fusion construct,wherein said fusion construct comprises a heterodimerization mutation.

According to an embodiment, the invention concerns the fusion construct,wherein said heterodimerization mutation is an F405L and/or K409Rmutation.

According to an embodiment, the invention concerns the fusion construct,wherein said fusion construct comprises:

-   a. A first chain comprising    -   i. a sequence according to SEQ ID No.: 1, SEQ ID No.: 2, or a        sequence with at least 90% sequence identity, preferably at        least 95% sequence identity, more preferred at least 98%        sequence identity to one of these sequences, and    -   ii. a sequence according to SEQ ID No.: 38, or a sequence with        at least 90% sequence identity, preferably at least 95% sequence        identity, more preferred at least 98% sequence identity to this        sequence, and-   b. A second chain comprising    -   iii. a sequence according to SEQ ID No.: 1, SEQ ID No.: 2, or a        sequence with at least 90% sequence identity, preferably at        least 95% sequence identity, more preferred at least 98%        sequence identity to one of these sequences, and    -   iv. a sequence according to SEQ ID No.: 38, or a sequence with        at least 90% sequence identity, preferably at least 95% sequence        identity, more preferred at least 98% sequence identity to this        sequence.

According to an embodiment, the invention concerns the fusion construct,wherein said fusion construct comprises:

-   a. A first chain comprising    -   i. a sequence according to SEQ ID No.: 3, SEQ ID No.: 4, or a        sequence with at least 90% sequence identity, preferably at        least 95% sequence identity, more preferred at least 98%        sequence identity to one of these sequences, and    -   ii. a sequence according to SEQ ID No.: 38, or a sequence with        at least 90% sequence identity, preferably at least 95% sequence        identity, more preferred at least 98% sequence identity to this        sequence, and-   b. A second chain comprising    -   iii. a sequence according to SEQ ID No.: 3, SEQ ID No.: 4, or a        sequence with at least 90% sequence identity, preferably at        least 95% sequence identity, more preferred at least 98%        sequence identity to one of these sequences, and    -   iv. a sequence according to SEQ ID No.: 38, or a sequence with        at least 90% sequence identity, preferably at least 95% sequence        identity, more preferred at least 98% sequence identity to this        sequence.

According to an embodiment, the invention concerns the fusion construct,wherein said fusion construct comprises:

-   a. A first chain comprising    -   i. a sequence according to SEQ ID No.: 1, SEQ ID No.: 2, or a        sequence with at least 90% sequence identity, preferably at        least 95% sequence identity, more preferred at least 98%        sequence identity to one of these sequences, and    -   ii. a sequence according to SEQ ID No.: 38, or a sequence with        at least 90% sequence identity, preferably at least 95% sequence        identity, more preferred at least 98% sequence identity to this        sequence, and-   b. A second chain comprising    -   iii. a sequence according to SEQ ID No.: 3, SEQ ID No.: 4, or a        sequence with at least 90% sequence identity, preferably at        least 95% sequence identity, more preferred at least 98%        sequence identity to one of these sequences, and    -   iv. a sequence according to SEQ ID No.: 40, or a sequence with        at least 90% sequence identity, preferably at least 95% sequence        identity, more preferred at least 98% sequence identity to this        sequence.

According to an embodiment, the invention concerns the fusion construct,wherein said fusion construct comprises:

-   a. A first chain comprising    -   i. a sequence according to SEQ ID No.: 1, SEQ ID No.: 2, or a        sequence with at least 90% sequence identity, preferably at        least 95% sequence identity, more preferred at least 98%        sequence identity to one of these sequences, and    -   ii. a linker sequence according to SEQ ID No.: 41, and    -   iii. a sequence according to SEQ ID No.: 65, or a sequence with        at least 90% sequence identity, preferably at least 95% sequence        identity, more preferred at least 98% sequence identity to this        sequence.-   b. A second chain comprising    -   v. a sequence according to SEQ ID No.: 1, SEQ ID No.: 2, or a        sequence with at least 90% sequence identity, preferably at        least 95% sequence identity, more preferred at least 98%        sequence identity to one of these sequences, and    -   vi. a linker sequence according to SEQ ID No.: 41, and    -   vii. a sequence according to SEQ ID No.: 65, or a sequence with        at least 90% sequence identity, preferably at least 95% sequence        identity, more preferred at least 98% sequence identity to this        sequence.

According to an embodiment, the invention concerns the fusion construct,wherein said fusion construct comprises:

-   a. A first chain comprising    -   i. a sequence according to SEQ ID No.: 3, SEQ ID No.: 4, or a        sequence with at least 90% sequence identity, preferably at        least 95% sequence identity, more preferred at least 98%        sequence identity to one of these sequences, and    -   ii. a linker sequence according to SEQ ID No.: 41, and    -   iii. a sequence according to SEQ ID No.: 65, or a sequence with        at least 90% sequence identity, preferably at least 95% sequence        identity, more preferred at least 98% sequence identity to this        sequence;-   b. A second chain comprising    -   iv. a sequence according to SEQ ID No.: 3, SEQ ID No.: 4, or a        sequence with at least 90% sequence identity, preferably at        least 95% sequence identity, more preferred at least 98%        sequence identity to one of these sequences, and    -   v. a linker sequence according to SEQ ID No.: 41, and    -   vi. a sequence according to SEQ ID No.: 65, or a sequence with        at least 90% sequence identity, preferably at least 95% sequence        identity, more preferred at least 98% sequence identity to one        of this sequence.

According to an embodiment, the invention concerns the fusion construct,wherein said fusion construct comprises:

-   a. A first chain comprising    -   i. a sequence according to SEQ ID No.: 1, SEQ ID No.: 2, or a        sequence with at least 90% sequence identity, preferably at        least 95% sequence identity, more preferred at least 98%        sequence identity to one of these sequences, and    -   ii. a linker sequence according to SEQ ID No.: 41, and    -   iii. a sequence according to SEQ ID No.: 65, wherein said        sequence ID No.: 65 comprises one or more of the mutations of        table 8-   b. A second chain comprising    -   iv. a sequence according to SEQ ID No.: 3, SEQ ID No.: 4, or a        sequence with at least 90% sequence identity, preferably at        least 95% sequence identity, more preferred at least 98%        sequence identity to one of these sequences, and    -   v. a linker sequence according to SEQ ID No.: 41, and    -   vi. a sequence according to SEQ ID No.: 65, wherein said        sequence ID No.: 65 comprises one or more of the mutations of        table 8.

According to an embodiment, the invention concerns the fusion construct,wherein the ratio of fusion construct to said drug and/or payload isselected among 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

According to an embodiment, the invention concerns the fusion construct,wherein said fusion construct comprises a kappa light chain according toSEQ ID No.: 51 or a lambda light chain according to SEQ ID No.: 52 or53.

According to an embodiment, the invention concerns a fusion construct,wherein said fusion construct is an IgG3 construct, and wherein saidIgG3 construct comprises a hinge region, wherein said hinge region hasbeen modified.

According to an embodiment, the invention concerns the fusion construct,wherein said hinge region comprises a sequence having a total of atleast 10% identity, at least 15%, at least 20%, at least 25%, at least30%, at least 35%, at least 40%, at least 45%, at least 50%, at least55%, at least 60%, at least 65%, at least 70%, at least 75%, at least80%, at least 85%, at least 90%, at least 95% or at least 99% identityto the sequence according to SEQ ID No.: 6 or SEQ ID No.: 8.

According to an embodiment, the invention concerns the fusion construct,wherein said fusion construct comprises the sequence according to SEQ IDNo.: 5, 7, 9, 10, 11, 12 and/or 13.

According to an embodiment, the invention concerns the fusion construct,wherein said hinge region comprises at least one free cysteine residue,at least two free cysteine residues or preferably at least three freecysteine residues.

According to an embodiment, the invention concerns the fusion construct,wherein said hinge region comprises a S228P mutation.

According to an embodiment, the invention concerns the fusion construct,wherein said hinge region comprises a sequence according to SEQ ID No.:6 and/or SEQ ID No.: 8 and/or SEQ ID No.: 68.

According to an embodiment, the invention concerns the fusion construct,wherein said fusion construct is used to detect phosphatidylserine.

According to an embodiment, the invention concerns the fusion construct,wherein said fusion construct is used to detect phosphatidylserine inthe blood of a subject.

According to an embodiment, the invention concerns the fusion construct,wherein said fusion construct comprises a sequence according to SEQ IDNo.: 1, and/or a sequence according to SEQ ID No.: 2.

According to an embodiment, the invention concerns the fusion construct,wherein said fusion construct is used to detect C-type lectin bindingmannan or fucan moieties.

According to an embodiment, the invention concerns the fusion construct,wherein said fusion construct is used to detect C-type lectin bindingmannan or fucan moieties in the blood of a subject.

According to an embodiment, the invention concerns the fusion construct,wherein said fusion construct comprises a sequence according to SEQ IDNo.: 3 and/or a sequence according to SEQ ID No.: 4.

According to an embodiment, the invention concerns a fusion construct, afusion protein or an antibody comprising the constant region(s) of IgG3and a hinge, wherein said hinge preferably is selected among an IgG1 orIgG4 hinge.

According to an embodiment, the invention concerns the fusion construct,fusion protein or antibody, comprising one or more heterodimerizationmutations.

According to an embodiment, the invention concerns the fusion construct,fusion protein or antibody, comprising heterodimerization mutationsinvolve positions 405 and/or 409 (EU numbering).

According to an embodiment, the invention concerns IgG3 homodimercomprising a hinge region, wherein said hinge region comprises asequence selected among SEQ ID No.: 6, 8 and 68.

According to an embodiment, the invention concerns IgG3 heterodimercomprising a hinge region, wherein said hinge region comprises asequence selected among SEQ ID No.: 6, 8 and 68.

According to an embodiment, the invention concerns IgG3, wherein saidIgG3 comprises a mutation at position 405 and/or position 409.

According to an embodiment, the invention concerns IgM heterodimersobtainable by changing the charge pairs of the CH2 and/or CH4 domains.

According to an embodiment, the invention concerns IgM heterodimers,comprising one or more of the mutations of Table 8.

According to an embodiment, the invention concerns the IgM, wherein saidIgM comprises a sequence according to SEQ ID No.: 64 and/or 65.

According to an embodiment, the invention concerns a fusion construct,wherein said fusion construct comprises an IgG3 homodimer, an IgG3heterodimer and/or an IgM heterodimer according to the invention.

According to an embodiment, the invention concerns the fusion construct,wherein said fusion construct is for use in the treatment of aninfection.

According to an embodiment, the invention concerns the fusion construct,wherein said infection is an infection caused by a virus, a parasite, abacterium, a fungi or a protozoan.

According to an embodiment, the invention concerns the fusion construct,wherein said virus is selected among an arborvirus, Zika virus, Denguevirus, West Nile virus, Ebola virus, influenza virus, influenza virusH1N1, Chikungunya virus, Enterovirus and Coronaviruses SARS-COV.

According to an embodiment, the invention concerns the fusion construct,wherein said bacteria is selected among mycobacterium tuberculosis andmycobacterium leprae.

According to an embodiment, the invention concerns the fusion construct,wherein said parasite is selected among Leishmaniasis and Malaria.

According to an embodiment, the invention concerns use of a fusionconstruct according to the invention for the treatment of an infection.

According to an embodiment, the invention concerns use, wherein saidinfections are selected among viral, bacterial and protozoan infections.

According to an embodiment, the invention concerns use, wherein thetreatment comprising administration of the fusion construct with anadministration form selected among subcutaneous, intradermal,intramuscular, oral and nasal.

According to an embodiment, the invention concerns use of IgG4 or a partof IgG4 for payload delivery, wherein said IgG4 has been modified tocomprise no Fc or wherein the activity of the Fc of said IgG4 has beennullified or diminished by one or more mutations.

According to an embodiment, the invention concerns the use, wherein saidIgG4 comprises one or more heterodimerization mutations.

According to an embodiment, the invention concerns the use, wherein saidIgG4 comprises one or more Cys mutations, preferably thereby allowingsite specific conjugation.

According to an embodiment, the invention concerns the use, wherein saidIgG4 comprises a Cys at position 339 (EU numbering).

According to an embodiment, the invention concerns a vaccine comprisinga fusion construct according to the invention.

According to an embodiment, the invention concerns a vaccine comprisinga mannan, a high mannose containing structure, a fucan and/or aphospholipid phosphatidylserine (PS).

According to an embodiment, the invention concerns the vaccine furthercomprising a β -glucan adjuvant to potentiate immune response.

According to an embodiment, the invention concerns the vaccine, for theprevention and/or treatment of an infection.

According to an embodiment, the invention concerns the vaccine, whereinsaid infection is caused by a virus, a parasite, a bacterium, a fungusor a protozoan.

According to an embodiment, the invention concerns the fusion constructand/or vaccine, wherein said fusion construct and/or vaccine allowsadministration through a route selected among subcutaneousadministration, intradermal administration, intramuscularadministration, oral administration and/or nasal administration.

According to an embodiment, the invention concerns a compositioncomprising a fusion construct according to the invention, optionallycomprising one or more excipients such as diluents, binders or carriers.

According to an embodiment, the invention concerns a method of treatingand/or preventing an infection in a subject, comprising a step ofadministration of a fusion construct and/or a vaccine and/or acomposition to the invention.

According to an embodiment, the invention concerns a method of screeningand/or monitoring progression of a disease in a subject, wherein saidmethod comprises the following steps:

-   i. Providing a blood sample from said subject.-   ii. Contacting said blood sample with a fusion construct according    to the invention.

According to an embodiment, the invention concerns an isolated nucleicacid molecule encoding a fusion construct according to the invention.

According to an embodiment, the invention concerns a recombinant vectorcomprising the nucleic acid molecule according to the invention.

According to an embodiment, the invention concerns a host cellcomprising the recombinant vector according to the invention.

According to an embodiment, the invention concerns a method to produce afusion construct according to the invention comprising a step ofculturing the host cell according to the invention in a culture mediumunder conditions allowing the expression of the fusion construct andseparating the fusion construct from the culture medium.

Additional embodiments of the invention are described below.

According to an embodiment, the invention concerns a fusion construct,wherein said fusion construct comprises a hinge region, wherein saidhinge region comprises any of the sequences as described below:

Construct Hinge region sequence IgG1 -KS--CDKTHT-----------CPPCPAP (SEQID NO. 73) IgG2 -K----------------CCVECPPCPAP (SEQ ID NO. 74) IgG3LKTPLGDTTHTPEPKSCDTPPPCPRCPAP (SEQ ID NO. 6) IgG4SKY--G--------------PPCPSCPAP (SEQ ID NO. 75) V-IGG2, -A, -B-KD---------------KTHTCPPCPAP (SEQ ID NO. 76) V-IGG2-C, -D, -E-K----------------YGPPCPPCPAP (SEQ ID NO. 77) V-IGG3, -A, -BSKY--G--------------PPCPPCPAP (SEQ ID NO. 78) V-IGG3-C, -D, -ELKT--GDTTHT-----------CPRCPAP (SEQ ID NO. 79) V-IGG4-A, -BSKY--G--------------PPCPPCPAP (SEQ ID NO. 80)

According to an embodiment, the invention concerns a fusion construct,wherein said fusion construct comprises an Fc heterodimerizationsequence at residue 405-409, wherein said Fc heterodimerization sequencecomprises a sequence according to SEQ ID No.: 48, 49 or 50.

IgG Fc heterodimerization sequences (residues 405-409) ConstructSequence IgG2 FLYSK SEQ ID No.: 48 V-IGG2/-C FLYSK SEQ ID No.: 48V-IGG2-A/-D FLYSR SEQ ID No.: 49 V-IGG2-B/-E LLYSK SEQ ID No.: 50 IgG3FLYSK SEQ ID No.: 48 V-IGG3/-C FLYSK SEQ ID No.: 48 V-IGG3-A/-D FLYSRSEQ ID No.: 49 V-IGG3-B/-E LLYSK SEQ ID No.: 50 IgG4 FLYSR SEQ ID No.:49 V-IGG4-A FLYSR SEQ ID No.: 49 V-IGG4-B LLYSK SEQ ID No.: 50

Immunoglobulins are glycoproteins composed of one or more units, eachcontaining four polypeptide chains: two identical heavy chains (HCs) andtwo identical light chains (LCs). The amino terminal ends of thepolypeptide chains show considerable variation in amino acid compositionand are referred to as the variable (V) regions to distinguish them fromthe relatively constant (C) regions. Each light chain consists of onevariable domain, VL, and one constant domain, CL. The heavy chainsconsist of a variable domain, VH, and three constant domains CH1, CH2and CH3. Heavy and light chains are held together by a combination ofnon-covalent interactions and covalent interchain disulfide bonds,forming a bilaterally symmetric structure. The V regions of H and Lchains comprise the antigen-binding sites of the immunoglobulin (Ig)molecules. Each Ig monomer contains two antigen-binding sites and issaid to be bivalent.

The Fab contains one complete L chain in its entirety and the V and CH1portion of one H chain. The Fab can be further divided into a variablefragment (Fv) composed of the VH and VL domains, and a constant fragment(Fb) composed of the CL and CH1 domains.

The H chain constant domain is generally defined as CH1-CH2-CH3 (IgG,IgA, IgD) with an additional domain (CH4) for IgM and IgE. As describedabove, the CH1 domain is located within the F(ab) region whereas theremaining CH domains (CH2—CH3 or CH2—CH4) comprise the Fc fragment. ThisFc fragment defines the isotype and subclass of the immunoglobulin.

CH3 domain: The terms CH3 domain and CH3 region are used interchangeableherein.

CH1 domain: The terms CH1 domain and CH1 region are used interchangeableherein.

Hinge region: The hinge region is the area of the heavy chains betweenthe first and second C region domains and is held together by disulfidebonds. A hinge region typically comprises between 10 and 30 amino acidresidues.

Linker: A linker might be a peptide linker or a non-peptide linker. Anexample of a peptide linker is a Gly/Ser peptide linker comprising afive amino acid residue unit, GGGGS (SEQ ID NO:71), that can be repeateda suitable amount of times. A linker might be a naturally occurringlinker or a synthetically produced linker. A linker might occurnaturally in a molecule or might be synthetically added to a molecule.

Antibody fragment: As used herein, an “antibody fragment” includes aportion of an intact antibody, such as, for example, the antigen-bindingor variable region of an antibody. Examples of antibody fragmentsinclude Fab, Fab′, F(ab′)2, and Fv fragments; triabodies; tetrabodies;linear antibodies; single-chain antibody molecules; and multi specificantibodies formed from antibody fragments. For example, antibodyfragments include isolated fragments, “Fv” fragments, consisting of thevariable regions of the heavy and light chains, recombinant single chainpolypeptide molecules in which light and heavy chain variable regionsare connected by a peptide linker (“ScFv proteins”), and minimalrecognition units consisting of the amino acid residues that mimic thehypervariable region. In many embodiments, an antibody fragment containssufficient sequence of the parent antibody of which it is a fragmentthat it binds to the same antigen as does the parent antibody; in someembodiments, a fragment binds to the antigen with a comparable affinityto that of the parent antibody and/or competes with the parent antibodyfor binding to the antigen. Examples of antigen binding fragments of anantibody include, but are not limited to, Fab fragment, Fab′ fragment,F(ab′)2 fragment, scFv fragment, Fv fragment, dsFv diabody, dAbfragment, Fd′ fragment, Fd fragment, and an isolated complementaritydetermining region (CDR) region. An antigen-binding fragment of anantibody may be produced by any means. For example, an antigen-bindingfragment of an antibody may be enzymatically or chemically produced byfragmentation of an intact antibody and/or it may be recombinantlyproduced from a gene encoding the partial antibody sequence.Alternatively, or additionally, antigen-binding fragment of an antibodymay be wholly or partially synthetically produced. An antigen-bindingfragment of an antibody may optionally comprise a single chain antibodyfragment. Alternatively, or additionally, an antigen-binding fragment ofan antibody may comprise multiple chains that are linked together, forexample, by disulfide linkages. An antigen-binding fragment of anantibody may optionally comprise a multi-molecular complex. A functionalantibody fragment typically comprises at least about 50 amino acids andmore typically comprises at least about 200 amino acids.

Antibody or fragment thereof: As used herein, an “antibody or fragmentthereof” refers to an antibody or antibody fragment as defined above.

Humanized antibodies: Humanized antibodies are antibodies from non-humanspecies whose protein sequences have been modified to increase theirsimilarity to antibody variants produced naturally in humans.

IMGT: the international ImMunoGeneTics information system, is aninternational reference in immunogenetics and immunoinformatics.

Single-chain Fv (scFv): Single-chain Fvs (scFvs) are widely known andused in the art. A single-chain Fv is a fusion protein of the variableregions of the heavy (VH) and light chains (VL) of immunoglobulins,often connected by a short linker peptide (see, e.g., see, e.g., BennyK. C. Lo (ed.), Antibody Engineering - Methods and Protocols, HumanaPress 2004, and references cited therein).

FIGURES

FIG. 1 shows TIM1 and CTLD constructs with enhanced ADCC, ADCP and CDC.

FIG. 2 shows TIM1 and CTLD constructs with T cell engager activity.

FIG. 3 shows TIM1 and CTLD constructs with furin inhibitor payload.

FIG. 4 shows TIM1 and CTLD constructs with IgM effector function.

FIGS. 5 a and 5 b shows SEC-HPLC analysis of VP019 and VP020respectively.

FIG. 6 a shows that VP025 consists of 4 distinct peaks. FIG. 6 b :intact mass spectrometry Fraction 3 from peak 3 (VP025-F3). FIG. 6 c :intact mass spectrometry: Fraction 4 from peak 4 (VP025-F4).

FIGS. 7 a and 7 b show the schematics and purity of VP300 and VP301 bySEC-HPLC.

FIG. 8 shows binding of SARS-CoV-2 S protein (D614G)

FIG. 9 shows binding of VP025-CT to viral proteins

FIGS. 10 a and 10 b show binding curves of VP019, VP020, VP025-CT(heterodimer mixture) and VP025-F4 (78% pure heterodimer) to abiotin-phosphatidyl serine and a select group of viral antigens.

FIG. 11 shows the structure of Hexa-D-arginine linker-compound andDecanoyl-RVKR-CMK linker compound

FIG. 12 shows the reaction scheme for the Decanoyl-RVKR-CMK linkercompound

FIGS. 13 a and b shows a mass-spectrogram demonstrating that conjugationof furin inhibitor payload to VP020 has been accomplished.

FIG. 14 a shows a neutralization assay for selected fusion proteins ofthe invention. For more details see example 16.

FIG. 14 b shows a neutralization assay for selected fusion protein ofthe invention. For more details see example 17.

All cited references are incorporated by reference.

The accompanying Figures and Examples are provided to explain ratherthan limit the present invention. It will be clear to the person skilledin the art that aspects, embodiments, claims and any items of thepresent invention may be combined.

Unless otherwise mentioned, all percentages are in weight/weight. Unlessotherwise mentioned, all measurements are conducted under standardconditions (ambient temperature and pressure). Unless otherwisementioned, test conditions are according to European Pharmacopoeia 8.0.

EXAMPLES Example 1: Selection of Recombinant Human TIM1 Fragment

Construct V-TIM1-1 was selected as residues 21-125 of the full lengthTIM-1 sequence (https://www.uniprot.org/uniprot/Q96D42), and V-TIM1-2was selected as residues 21-127. V-TIM1-2 contains an extra two Proresidues at the C-terminal domain boundary.

TABLE 1 Sequences of Recombinant human TIM1 fragment Construct SequenceMw Predicted pl V-TIM1-1 SVKVGGEAGPSVTLPCHYSGAVTSMCWNRGSCSLFTCQNGIVWTNGTHVTYRKDTRYKLLGDLSRRDVSLTIENT AVSDSGVYCCRVEHRGWFNDMKITVSLEIVSEQ ID No.: 1 11.6 KDa 8.26 V-TIM1-2SVKVGGEAGPSVTLPCHYSGAVTSMCWNRGSCSLFTCQNGIVWTNGTHVTYRKDTRYKLLGDLSRRDVSLTIENT AVSDSGVYCCRVEHRGWFNDMKITVSLEIVPPSEQ ID No.: 2 11.8 KDa 8.26

Example 2: Selection of Recombinant Human C-Type Lectin Domain (CTLD)Fragment of DC-SIGN (CD209)

Construct V-CTLD-1 was selected as residues 250-385 of the full lengthDC-SIGN sequence (https://www.uniprot.org/uniprot/Q9NNX6), and V-CTLD-2was selected as residues 254-383. V-CTLD-1 contains 4 internal disulfidebonds, whereas V-CTLD-2 contains 3 internal disulfide bonds.

TABLE 2 Sequences of Recombinant human CTLD fragment of DC-SIGNConstruct Sequence MW Predicted pl V-CTLD-1ERLCHPCPWEWTFFQGNCYFMSNSQRNWHDSITACKEVGAQLVVIKSAEEQNFLQLQSSRSNRFTWMGLSDLNQEGTWQWVDGSPLLPSFKQYWNRGEPNNVGEEDCA EFSGNGWNDDKCNLAKFWICKKSAASCS SEQ IDNo.: 3 15.7 KDa 5.12 V-CTLD-2 HPCPWEWTFFQGNCYFMSNSQRNWHDSITACKEVG AQLVVIKSAEEQN FLQLQSSRSN RFTWMG LSDLNQEG TWQWVDGSPLLPSFKQYWN RGEPN NVGEEDCAEFSG NGWNDDKCNLAKFWICKKSAAS SEQ ID No.: 4 15.0 KDa 5.08

Example 3: Design of TIM-1 and CTLD Constructs With IgG3 EffectorFunctions

Among all human IgG subclasses, IgG3 has the highest effector functionsin terms of ADCC, ADCP and CDC(https://www.frontiersin.org/articles/10.3389/fimmu.2014.00520/full).IgG3 has not typically been used for therapeutics because of the shortserum half-life due to proteolytic cleavage of the prolonged hingeregion between the CH1 and CH2 domains. To utilize the strong effectorfunctions of the IgG3 subclass, the V-IGG3 construct was designed wherethe IgG3 hinge (LKTPLGDTTHTPEPKSCDTPPPCPRCPAP) (SEQ ID NO. 6) wasreplaced with an IgG4 hinge sequence containing an IgG4 hinge S228Pmutation to prevent Fab arm exchange (SKYGPPCPPCPAP) (SEQ ID NO. 8) oran IgG1-like hinge (KTGDTTHTCPRCPAP) (SEQ ID NO. 68).

Heterodimeric V-IGG3 constructs were designed based on including K409R(on one half-antibody) and F405L (on second antibody) mutation in theCH3 domains (https://www.nature.com/articles/nprot.2014.169). Each halfantibody is first generated as a single homodimer, then mixed togetherand allowed to recombine as heterodimers under reducing and oxidizingconditions. The resulting sequences are noted as V-IGG3-A and V-IGG3-Band pair together, or V-IGG3-D and V-IGG3-E that pair together.Sequences are found in Table 3, including truncated version that includea (GGGGS)3 linker (SEQ ID NO. 41) to replace the CH1 domains.

TABLE 3 Modified IgG3 domains Construct Sequence Notes WT huIgG3CH1-CH2-CH3 ASTKGPSVFPLAPCSRSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYTC NVN H KPSNTKVDKRVE LKTPLGDTTHTPEPKSCDTPPPCPR CPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFKWYVDGVEVHNAKTKPREEQYNSTFRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESSGQPENNYNTTPPMLDSDGSFFLYSKLTVDKSRWQQGNIFSCSVM HEALHNRFTQKSLSLSPGK SEQ ID No.:5 Hinge region underlined as SEQ ID No.: 6 V-IGG3ASTKGPSVFPLAPCSRSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYTCNVNHKPSNTKVDKRVESKYGPPCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFKWYVDGVEVHNAKTKPREEQYNSTFRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESSGQPENNYNTTPPMLDSDGSFFLYSKLTVDKSRWQQGNIFSCSVMHEALHNRFTQKSLSLSPG K SEQ ID No.: 7 Hinge regionunderlined (SEQ ID No.: 8) with IgG4 hinge S228P mutation in boldV-lGG3-Fc GGGGSGGGGSGGGGSKYGPPCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFKWYVDGVEVHNAKTKPREEQYNSTFRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESSGQPENNYNTTPPMLDSDGSFFL YSKL TVDKSRWQQGNI FSCSVM HEALHNRFTQKSLSLSPG K SEQ ID No.: 9 Same as above, but with linker and fc onlyV-IGG3-A ASTKGPSVFPLAPCSRSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYTCNVNHKPSNTKVDKRVESKYGPPCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFKWYVDGVEVHNAKTKPREEQYNSTFRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESSGQPENNYNTTPPMLDSDGSFFLYSRLTVDKSRWQQGNIFSCSVMHEALHNRFTQKSLSLSPG K SEQ ID No.: 10 K409RV-lGG3-A-Fc GGGGSGGGGSGGGGSKYGPPCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFKWYVDGVEVHNAKTKPREEQYNSTFRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESSGQPENNYNTTPPMLDSDGSFFL Same as above, but with linkerand fc only YSRLTVDKSRWQQGNIFSCSVMHEALHNRFTQKSLSLSPG K SEQ ID No.: 11V-IGG3-B ASTKGPSVFPLAPCSRSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYTCNVNHKPSNTKVDKRVESKYGPPCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFKWYVDGVEVHNAKTKPREEQYNSTFRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESSGQPENNYNTTPPMLDSDGSFLL YSKL TVDKSRWQQGNI FSCSVM HEALHNRFTQKSLSLSPG K SEQ ID No.: 12 F405L V-IGG3-B-FcGGGGSGGGGSGGGGSKYGPPCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFKWYVDGVEVHNAKTKPREEQYNSTFRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESSGQPENNYNTTPPMLDSDGSFLL YSKL TVDKSRWQQGNI FSCSVM HEALHNRFTQKSLSLSPG K SEQ ID No.: 13 Same as above, but with linker and fconly V-IGG3-C ASTKGPSVFPLAPCSRSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYTCNVNHKPSNTKVDKRVELKTGDTTHTCPRCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFKWYVDGVEVHNAKTKPREEQYNSTFRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESSGQPENNYNTTPPMLDSDGSFFLYSKLTVDKSRWQQGNIFSCSVMHEALHNRFTQKSL SLSPGK SEQ ID No.: 42 Utilizesan IgG1-like hinge V-IGG3-C-Fc GGGGSGGGGSGGGGSKTGDTTHTCPRCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFKWYVDGVEVHNAKTKPREEQYNSTFRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESSGQPENNYNTTPPMLDSDGSFFLYSKLTVDKSRWQQGNIFSCSVMHEALHNRFTQKSLSL SPGK SEQ ID No.: 43 Same asabove, but with linker and fc only V-IGG3-DASTKGPSVFPLAPCSRSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYTCNVNHKPSNTKVDKRVELKTGDTTHTCPRCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFKWYVD GVEVH NAKTKPREEQYNSTFRVVSVLTVLHQDWLNG KEY KCKVSNKALPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESSGQPEN NYNTTPPM LDSD K409RGSFFLYSRLTVDKSRWQQGNIFSCSVMHEALHNRFTQKSL SLSPGK SEQ ID No.: 44V-IGG3-D-Fc GGGGSGGGGSGGGGSKTGDTTHTCPRCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFKWYVDGVEVHNAKTKPREEQYNSTFRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESSGQPENNYNTTPPMLDSDGSFFLYSRLTVDKSRWQQGNIFSCSVMHEALHNRFTQKSLSL SPGK SEQ ID No.: 45 Same asabove, but with linker and fc only V-IGG3-EASTKGPSVFPLAPCSRSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYTCNVNHKPSNTKVDKRVELKTGDTTHTCPRCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFKWYVD GVEVH NAKTKPREEQYNSTFRVVSVLTVLHQDWLNG KEY KCKVSNKALPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESSGQPENNYNTTPPMLDSDGSFLLYSKLTVDKSRWQQGNIFSCSVMHEALHNRFTQKSL SLSPGK SEQ ID No.: 46 F405LV-IGG3-E-Fc GGGGSGGGGSGGGGSKTGDTTHTCPRCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFKWYVDGVEVHNAKTKPREEQYNSTFRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESSGQPENNYNTTPPMLDSDGSFLLYSKLTVDKSRWQQGNIFSCSVMHEALHNRFTQKSLSL SPGK SEQ ID No.: 47 Same asabove, but with linker and fc only

TIM1 and CTLD fusion proteins were designed with the modified IgG3-Fcdomains and are depicted in FIG. 1 and Table 4.

TABLE 4 Sequences of TIM-1 and CTLD constructs with enhanced ADCC, ADCPand CDC Construct Chain 1 Chain 2 VIT-300 (V-TIM1-1/V-TIM1-2)-V-IGG3-Fc/V-IGG3-C-Fc Same as Chain 1 VIT-301 (V-CTLD-1/V-CTLD-2)-V-IGG3-Fc/ V-IGG3-C-Fc Same as Chain 1 VIT-302 (V-TIM1-1/V-TIM1-2)-V-IGG3-A-Fc/ V-IGG3-D-Fc (V-CTLD-1/V-CTLD-2) -V-IGG3-B-Fc/ V-IGG3-E-Fc

Example 4. Design of TIM-1 and CTLD Constructs With T Cell EngagingActivity

Additional constructs were designed to engage T cell effector functionsby fusing the TIM-1 and CTLD with a single anti-CD3 scFv. The designsare shown in FIG. 2 and Table 5.

TABLE 5 Sequences of TIM-1 and CTLD constructs with T cell engageractivity Construct Chain 1 Chain 2 VIT-303(V-TIM1-1/V-TIM1-2)-(V-IGG4-A-Fc/ V-IGG2-A-Fc/V-IGG2-D-Fc)(V-TIM1-1/V-TIM1-2)-(V-IGG4-B-Fc/V-IGG2-B-Fc/V-IGG2-E-Fc)-GGGGSGGGGSGGGGS (SEQ ID No.: 41)-(anti-CD3scFv) VIT-304 (V-CTLD-1/V-CTLD-2)-(V-IGG4-A-Fc/ V-IGG2-A-Fc/V-IGG2-D-Fc) (V-CTLD-1/V-CTLD-2)-(V-IGG4-B-Fc/V-IGG2-B-Fc/V-IGG2-E-Fc)-GGGGSGGGGSGGGGS (SEQ ID No.: 41)-(anti-CD3scFv) VIT-305 (V-TIM1-1/V-TIM1-2)-(V-IGG4-A-Fc/ V-IGG2-A-Fc/V-IGG2-D-Fc) (V-CTLD-1/V-CTLD-2)-(V-IGG4-B-Fc/ V-IGG2-B-Fc/V-IGG2-E-Fc)-GGGGSGGGGSGGGGS (SEQ ID No.: 41)-(anti-CD3 scFv) VIT-306(V-TIM1-1/V-TIM1-2)-(V-IGG4-B-Fc/ V-IGG2-B-Fc/V-IGG2-E-Fc)-GGGGSGGGGSGGGGS (SEQ ID No.: 41)-(anti-CD3 scFv)(V-CTLD-1/V-CTLD-2)-GGGGSGGGGSGGGGS (SEQ ID No.: 41)-(V-IGG4-A-Fc/V-IGG2-A-Fc /V-IGG2-D-Fc)

TABLE 6 Anti-CD3 scFv sequences are described below Construct SequenceVCD3-H1L1 QVQLVQSGGGVVQPGRSLRLSCAASGYTFTRYTMHWVRQAPGKGLEWVGYINPSRGYTNYNDSVKGRFTISTDKSKNTAYLOQMNSLRAEDTAVYYCARYYDDHYSLDYWGQGTTVTVSSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCQASSSVSYMNWYQQKPGKAPKRWIYDTSKLASGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQQWSSNPFTFGQGTKLEIK (SEQ ID NO: 18) VCD3-H1L1-DSQVQLVQSGGGVVQPGRSLRLSCAASGYTFTRYTMHWVRQAPGKCLEWVGYINPSRGYTNYNDSVKGRFTISTDKSKNTAYLOQMNSLRAEDTAVYYCARYYDDHYSLDYWGQGTTVTVSSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCQASSSVSYMNWYQQKPGKAPKRWIYDTSKLASGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQQWSSNPFTFGCGTKLEIK (SEQ ID NO: 19) VCD3-H1L2QVQLVQSGGGVVQPGRSLRLSCAASGYTFTRYTMHWVRQAPGKGLEWVGYINPSRGYTNYNDSVKGRFTISTDKSKNTAYLOQMNSLRAEDTAVYYCARYYDDHYSLDYWGQGTTVTVSSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSEIVLTQSPATLSLSPGERATLSCRASSSVSYMNWYQQKPGQAPRRLIYDTSKRATGIPARFSGSGSGTDYTLTISSLEPEDAAVYYCQQWSSNPFTFGQGTKLEIK (SEQ ID NO: 20) VCD3-H1L2-DSQVQLVQSGGGVVQPGRSLRLSCAASGYTFTRYTMHWVRQAPGKCLEWVGYINPSRGYTNYNDSVKGRFTISTDKSKNTAYLOQMNSLRAEDTAVYYCARYYDDHYSLDYWGQGTTVTVSSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSEIVLTQSPATLSLSPGERATLSCRASSSVSYMNWYQQKPGQAPRRLIYDTSKRATGIPARFSGSGSGTDYTLTISSLEPEDAAVYYCQQWSSNPFTFGCGTKLEIK (SEQ ID NO: 21) VCD3-H1L3QVQLVQSGGGVVQPGRSLRLSCAASGYTFTRYTMHWVRQAPGKGLEWVGYINPSRGYTNYNDSVKGRFTISTDKSKNTAYLOQMNSLRAEDTAVYYCARYYDDHYSLDYWGQGTTVTVSSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSEIQLTQSPATLSLSPGERATLSCRASSSVSYMNWYQQKPGQAPRRWIYDTSKLATGIPARFSGSGSGTDYTLTISSLEPEDAAVYYCQQWSSNPFTFGQGTKLEIK (SEQ ID NO: 22) VCD3-H1L3-DSQVQLVQSGGGVVQPGRSLRLSCAASGYTFTRYTMHWVRQAPGKCLEWVGYINPSRGYTNYNDSVKGRFTISTDKSKNTAYLQMNSLRAEDTAVYYCARYYDDHYSLDYWGQGTTVTVSSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSEIQLTQSPATLSLSPGERATLSCRASSSVSYMNWYQQKPGQAPRRWIYDTSKLATGIPARFSGSGSGTDYTLTISSLEPEDAAVYYCQQWSSNPFTFGCGTKLEIK (SEQ ID NO: 23) VCD3-H2L1QVQLVQSGAEVKKPGASVKVSCKASGYTFTRYTMHWVRQAPGQGLEWMGYINPSRGYTNYNQKFQGRVTMTTDKSTSTAYMELSSLRSEDTAVYYCARYYD DHYSLDYWGQGTTVTVSSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCQASSSVSYMNWYQQKPGKAPKRWIYDTSKLASGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQQWSSNPFTFGQGTKLEIK (SEQ ID NO: 24) VCD3-H2L1-DSQVQLVQSGAEVKKPGASVKVSCKASGYTFTRYTMHWVRQAPGQCLEWMGYINPSRGYTNYNQKFQGRVTMTTDKSTSTAYMELSSLRSEDTAVYYCARYYDDHYSLDYWGQGTTVTVSSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCQASSSVSYMNWYQQKPGKAPKRWIYDTSKLASGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQQWSSNPFTFGCGTKLEIK (SEQ ID NO: 25) VCD3-H2L2QVQLVQSGAEVKKPGASVKVSCKASGYTFTRYTMHWVRQAPGQGLEWMGYINPSRGYTNYN QKFQGRVTMTTDKSTSTAYMELSSLRSEDTAVYYCARYYDDHYSLDYWGQGTTVTVSSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSEIVLTQSPATLSLSPGERATLSCRASSSVSYMNWYQQKPGQAPRRLIYDTSKRATGIPARFSGSGSGTDYTLTISSLEPEDAAVYYCQQWSSNPFTFGQGTKLEIK (SEQ ID NO: 26) VCD3-H2L2-DSQVQLVQSGAEVKKPGASVKVSCKASGYTFTRYTMHWVRQAPGQCLEWMGYINPSRGYTNYNQKFQGRVTMTTDKSTSTAYMELSSLRSEDTAVYYCARYYDDHYSLDYWGQGTTVTVSSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSEIVLTQSPATLSLSPGERATLSCRASSSVSYMNWYQQKPGQAPRRLIYDTSKRATGIPARFSGSGSGTDYTLTISSLEPEDAAVYYCQQWSSNPFTFGCGTKLEIK (SEQ ID NO: 27) VCD3-H2L3QVQLVQSGAEVKKPGASVKVSCKASGYTFTRYTMHWVRQAPGQGLEWMGYINPSRGYTNYNQKFQGRVTMTTDKSTSTAYMELSSLRSEDTAVYYCARYYDDHYSLDYWGQGTTVTVSSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSEIQLTQSPATLSLSPGERATLSCRASSSVSYMNWYQQKPGQAPRRWIYDTSKLATGIPARFSGSGSGTDYTLTISSLEPEDAAVYYCQQWSSNPFTFGQGTKLEIK (SEQ ID NO: 28) VCD3-H2L3-DSQVQLVQSGAEVKKPGASVKVSCKASGYTFTRYTMHWVRQAPGQCLEWMGYINPSRGYTNYNQKFQGRVTMTTDKSTSTAYMELSSLRSEDTAVYYCARYYDDHYSLDYWGQGTTVTVSSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSEIQLTQSPATLSLSPGERATLSCRASSSVSYMNWYQQKPGQAPRRWIYDTSKLATGIPARFSGSGSGTDYTLTISSLEPEDAAVYYCQQWSSNPFTFGCGTKLEIK (SEQ ID NO: 29) VCD3-H3L1QVQLVQSGAEVKKPGASVKVSCKASGYTFTRYTMHWVRQSPGQGLEWMGYINPSRGYTNYNQKFQGRVTMTTDKSTSTAYMELSSLRSEDTAVYYCARYYDDHYSLDYWGQGTTVTVSSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCQASSSVSYMNWYQQKPGKAPKRWIYDTSKLASGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQQWSSNPFTFGQGTKLEIK (SEQ ID NO: 30) VCD3-H3L1-DSQVQLVQSGAEVKKPGASVKVSCKASGYTFTRYTMHWVRQSPGQCLEWMGYINPSRGYTNYNQKFQGRVTMTTDKSTSTAYMELSSLRSEDTAVYYCARYYDDHYSLDYWGQGTTVTVSSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCQASSSVSYMNWYQQKPGKAPKRWIYDTSKLASGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQQWSSNPFTFGCGTKLEIK (SEQ ID NO: 31) VCD3-H3L2QVQLVQSGAEVKKPGASVKVSCKASGYTFTRYTMHWVRQSPGQGLEWMGYINPSRGYTNYNQKFQGRVTMTTDKSTSTAYMELSSLRSEDTAVYYCARYYDDHYSLDYWGQGTTVTVSSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSEIVLTQSPATLSLSPGERATLSCRASSSVSYMNWYQQKPGQAPRRLIYDTSKRATGIPARFSGSGSGTDYTLTISSLEPEDAAVYYCQQWSSNPFTFGQGTKLEIK (SEQ ID NO: 32) VCD3-H3L2-DSQVQLVQSGAEVKKPGASVKVSCKASGYTFTRYTMHWVRQSPGQCLEWMGYINPSRGYTNYNQKFQGRVTMTTDKSTSTAYMELSSLRSEDTAVYYCARYYDDHYSLDYWGQGTTVTVSSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSEIVLTQSPATLSLSPGERATLSCRASSSVSYMNWYQQKPGQAPRRLIYDTSKRATGIPARFSGSGSGTDYTLTISSLEPEDAAVYYCQQWSSNPFTFGCGTKLEIK (SEQ ID NO: 33) VCD3-H3L3QVQLVQSGAEVKKPGASVKVSCKASGYTFTRYTMHWVRQSPGQGLEWMGYINPSRGYTNYNQKFQGRVTMTTDKSTSTAYMELSSLRSEDTAVYYCARYYDDHYSLDYWGQGTTVTVSSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSEIQLTQSPATLSLSPGERATLSCRASSSVSYMNWYQQKPGQAPRRWIYDTSKLATGIPARFSGSGSGTDYTLTISSLEPEDAAVYYCQQWSSNPFTFGQGTKLEIK (SEQ ID NO: 34) VCD3-H3L3-DSQVQLVQSGAEVKKPGASVKVSCKASGYTFTRYTMHWVRQSPGQCLEWMGYINPSRGYTNYNQKFQGRVTMTTDKSTSTAYMELSSLRSEDTAVYYCARYYDDHYSLDYWGQGTTVTVSSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSEIQLTQSPATLSLSPGERATLSCRASSSVSYMNWYQQKPGQAPRRWIYDTSKLATGIPARFSGSGSGTDYTLTISSLEPEDAAVYYCQQWSSNPFTFGCGTKLEIK (SEQ ID NO: 35)

Example 5. Design of TIM-1 and CTLD Constructs With Furin InhibitorPayload Delivery

Site specific addition of drug payloads to the antibody Fc region wasdevised by analysis of the co-crystal structure of a human IgG1 Fc withthe 3-helix bundle of bacterial protein A (PDB structure 5U4Yhttps://www.rcsb.org/sequence/5U4Y). Computational modelling revealedthat A339C would have a stabilizing effect to the structure and S337C orK340C would have a neutral effect to the stability of the Fc domain.A339C was chosen as the site for site specific conjugation.

TABLE 7 IgG4 sequences with engineered free cys for site specificpayload conjugation Construct Sequence Notes V-IGG4-ADC-AASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPE PVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYG PPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKT KPREEQFNSTYRVVSVLTVLHQDWLNG KEYKCAVSNKGLPSSIEKTISKCKGQPREPQVYTLPPSQEE MTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNV FSCSVMHEALHNHYTQKSLSLSLGK SEQ ID No.:37 S228P FALA (F234A, L235A) K322A Naturally contains F405 and R409A339C V-IGG4-ADC-A-Fc GGGGSGGGGSGGGGSKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDP EVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKGLPSSIEKTISK CKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFF Same as above, but with linker and fconly V-IGG4-ADC-B ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVV TVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTP EVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCA VSNKGLPSSIEKTISKCKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPEN NYKTTPPVLDSDGSFLLYSKLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID No.: 39 S228P FALA (F234A, L235A) K322AF405L, R409K A339C V-IGG4-ADC-B-Fc GGGGSGGGGSGGGGSKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDP EVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKGLPSSIEKTISK CKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFL LYSKLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID No.: 40 Same as above, but with linker and fc only

TIM1 and CTLD fusion proteins with Fc domain with payload conjugationsites were designed and are shown in FIG. 3 and Table 8.

TABLE 8 Sequences of TIM1 and CTLD therapeutic proteins with free cysfor payload conjugation Construct Chain 1 Chain 2 VIT-307(V-TIM1-1/V-TIM1-2) -V-IGG4-ADC-A-Fc Same as Chain 1 VIT-308(V-CTLD-1/V-CTLD-2) -V-IGG4-ADC-A-Fc Same as Chain 1 VIT-309(V-TIM1-1/V-TIM1-2) -V-IGG4-ADC-A-Fc (V-CTLD-1/V-CTLD-2)-V-IGG4-ADC-B-Fc

Example 6. Furin Linkers

Decanoyl-Arg-Val-Lys-Arg-chloromethylketone (dec-RVKR-cmk) (SEQ ID NO.81) or hexa-D-arginine (D6R) were linked to TIM-1 and CTLD constructsusing cleavable linkers such as acid sensitive N-acyl-hydrazone orenzyme sensitive malemeide-conjugated dipeptides, valine-alanine,valine-citrulline, or phenylalanine-Lysine.

Acid sensitive linkers are cleaved in the lysosome acidic environmentafter internalization of the construct. This strategy has been used intwo approved ADCs, Gemtuzumab ozogamicin and Inotuzumab ozogamicin.Lysosomal protease sensitive dipeptides release the drug after cleavageby proteases such as cathepsin B- lysosomal protease. This type oflinker chemistry has been used for FDA approved Brentuximab vedotin.

Linkage to the polypeptide of antibodies is done through thenucleophilic groups of lysine or cysteine by random conjugation,generating a heterogeneous mixture of conjugates, or by site-directedconjugation to engineered cysteines, reducing the heterogeneity of theproduct to an antibody-drug ratio (ADR) of 1 or 2.

The nucleophilic reactivity of the thiol functionality of a Cys residueto a maleimide group is about 1000 times higher compared to any otheramino acid functionality in a protein, such as amino group of lysineresidues or the N-terminal amino group. Thiol specific functionality inmaleimide reagents may react with amine groups, but higher pH (>9.0) andlonger reaction times are required (Garman, 1997, Non-RadioactiveLabelling: A Practical Approach, Academic Press, London).

The first FDA approved site-directed ADC through engineered cysteineswas vadastuximab talirine (Seattle Genetics).

TABLE 9 Linker Chemistry Residue Spacer 1 Linker Spacer 2 Drug Cysteine,engineered Cysteine Maleimidocaproyl (mc), maleimidomethyl VC, VA, PLpara-amino benzyloxycarbonyl (PABC) hexa-D-arginine, dec-RVKR-cmkcyclohexane- 1-carboxylate (comprising SEQ ID NO. 81) Lysine NAN-acyl-hydrozone, N-succinimidyl-4-(2-pyridyldithio) Butanoate-disulfide(SPDB-disulfide), maleimidomethyl cyclohexane-1-carboxylate, sulfo-SPDBNA hexa-D-arginine, dec-RVKR-cmk (comprising SEQ ID NO. 81) Spacer 1:The purpose of the mc spacer is to provide enough room so that the vcgroup can be recognized by cathepsin B, which cleaves thecitrulline-PABC amide bond. Spacer 2: Self-immolative spacer

Example 7. Fusion Proteins With IgM Constant Regions

IgM molecules have robust Fc effector functions, particularly with CDC.IgM molecules naturally homodimerize and then covalently associate intopentamers or hexamers. IgM do not contain hinge regions like IgGmolecules and instead contain an extra CH domain (CH1-CH2-CH3-CH4). Thehomodimeric heavy chains come together at the CH2 and CH4 domains. Basedon visual analyses of the crystal structure of the murine IgM CH2 domain(pdb 4JVU), the crystal structure of the murine IgM CH4 domain (pdb4JVW), and a sequence alignment of the human IgM CH2 and CH4 sequenceswith the homologous mouse sequences, mutations were designed to induceIgM heavy chain heterodimerization by inducing charge differences at thehomodimerization interfaces.

Sequence of human IgM constant region, numbered residues 1-453 byuniprot (www_uniprot.org/uniprot/P01871):

GSASAPTLFPLVSCENSPSDTSSVAVGCLAQDFLPDSITFSWKYKNNSDISSTRGFPSVLRGGKYAATSQVLLPSKDVMQGTDEHVVCKVQHPNGNKEKNVPLPVIAELPPKVSVFVPPRDGFFGNPRKS K LIC Q ATGFSPRQIQVSWLREGKQVGSGVTTDQVQAEAKESGPTTYKVTSTLTIKESDWLGQSMFTCRVDHRGLTFQQNASSMCVPDQDTAIRVFAIPPSFASIFLTKSTKLTCLVTDLTTYDSVTISWTRQNGEAVKTHTNISESHPNATFSAVGEASICEDDWNSGERFTCTVTHTDLPSPLKQTISRPKGVALHRPDVYLLPPAREQLNLRESATIT CLV TGFSPADVFVQWMQRGQPLSPEKYVTSAPMP E PQAPGRYFAHSILTVSEEEWNTGETYTCVVAHEALPNRVTERTVDKSTGKPTLYNVSLVMSDTAG TCY SEQ ID No.: 64

Sequence of IgM CH2-CH3-CH4 which can used for fusing to antibodyfragments (Fab, scFv, VHH, etc) or targeting proteins (TIM-1,CTLD/DC-SIGN) for adding IgM effector functions (residues 105-453):V-IGM

VIAELPPKVSVFVPPRDGFFGNPRKSKLICQATGFSPRQIQVSWLREGKQVGSGVTTDQVQAEAKESGPTTYKVTSTLTIKESDWLGQSMFTCRVDHRGLTFQQONASSMCVPDQDTAIRVFAIPPSFASIFLTKSTKLTCLYVTDLTTYDSVTISWTRQNGEAVKTHTNISESHPNATFSAVGEASICEDDWNSGERFTCTVTHTDLPSPLKQTISRPKGVALHRPDVYLLPPAREQLNLRESATITCLVTGFSPADVFVQWMQRGQPLSPEKYVTSAPMPEPQAPGRYFAHSILTVSEEEWNTGETYTCVVAHEALPNRVTERTVDKSTGKPTLYNVSLVMSDTAGTC Y SEQID No.: 65

Based on the structural analysis, the underlined residues K131 and Q135were found to be in close proximity in the CH2:CH2 interface, andresidues T354 and E385 were found to be in close proximity in theCH4:CH4 interface. The following mutations were made to alter the chargepattern in V-IGM-A and V-IGM-B to induce heterodimer formation of A:Band repel the formations of A:A or B:B.

TABLE 10 IgM constant region mutations to induce heavy chain heterodimerformation Position Wildtype residue in V-IGM V-IGM-A V-IGM-B 131 K K/R/HD/E 135 Q K/R/H D/E 354 T D/E K/R/H 385 E D/E K/R/H

TIM1 and CTLD fusion proteins with IgM effector functions were designedand shown in FIG. 4 and Table 11.

TABLE 11 Sequences of TIM1 and CTLD therapeutic proteins with IgMeffector functions Construct Chain 1 Chain 2 VIT-310 (V-TIM1-1/V-TIM1-2)-GGGGSGGGGSGGGGS (SEQ ID No.: 41)-V-IGM Same as Chain 1 VIT-311(V-CTLD-1/V-CTLD-2) -GGGGSGGGGSGGGGS (SEQ ID No.: 41) -V-IGM Same asChain 1 VIT-312 (V-TIM1-1/V-TIM1-2) -GGGGSGGGGSGGGGS (SEQ ID No.: 41)-V-IGM-A (V-CTLD-1/V-CTLD-2) -GGGGSGGGGSGGGGS (SEQ ID No.: 41)-V-IGM-B

Example 8: Expression and Purification of VP011-VP020

The 10 proteins from [Table 1 and FIGS. 1-3 ] were expressed and batchpurified form 2.5 mL ExpiCHO cultures using Protein A/G magnetic agarosebeads. Expression yields and % monomeric purity are shown in Table 12.

TABLE 12 Small scale expression of protein constructs Protein Name GeneName Description Fc domain Format Yield (µg) %Purity by SEC-HPLC VP011TM-G1 V-TIM1-1 with V-IGG1-Fc IgG1 VIT-300-IgG1 143 28.6 VP012 TM-G3V-TIM1-1 with V-IGG3-D-Fc IgG3 VIT-300-IgG3 150 34 VP013 CT-G1 V-CTLD-1with IgG1-Fc IgG1 VIT-301-IgG1 209 56.5 VP014 CT-G3 V-CTLD-1 withV-IGG3-E-Fc IgG3 VIT-301-IgG3 225 73.4 VP015 TM-G4-A V-TIM1-1 withV-IgG4-A-Fc IgG4 VIT-300-IgG4 113 11 VP016 TM-G4-A-F V-TIM1-1 withV-IgG4-A-Fc-CD3 (H3L3) IgG4 73 16.8 VP017 CT-G4-B V-CTLD-1 withV-IgG4-B-Fc IgG4 VIT-301-IgG4 386 73.1 VP018 CT-G4-B-F V-CTLD-1 withV-IgG4-B-Fc-CD3 (H3L3) IgG4 290 74.4 VP019 TM-G4-A-DC V-TIM1-1 withV-IGG4-ADC-A-Fc IgG4 VIT-307 77 11.5 VP020 CT-G4-B-DC V-CTLD-1 withV-IGG4-ADC-B-Fc IgG4 VIT-308 645 60.9

Larger scale preps were done in ExpiCHO cells for VP011 (100 mL), VP012(100 mL), VP013 (100 mL), VP014 (100 mL), VP019 (1L) and VP020 (250 mL).VP011, VP019 and VP020 were purified by MabSelect SuRe protein A resincolumn chromatography. VP012, VP013 and VP014 were purified by HiTrapProtein G resin column chromatography. Expression yields and % monomericpurity are shown in Table 13.

TABLE 13 Larger scale expression of protein constructs Protein Name GeneName Description Fc domain Format Yield (mg) %Purity by SEC-HPLC VP011TM-G1 V-TIM1-1 with V-IGG1-Fc IgG1 VIT-300-IgG1 0.78 78.5^(∗) VP012TM-G3 V-TIM1-1 with V-IGG3-D-Fc IgG3 VIT-300-IgG3 9.18 68.0^(∗) VP013CT-G1 V-CTLD-1 with IgG1-Fc IgG1 VIT-301-IgG1 15.6 59.3 VP014 CT-G3V-CTLD-1 with V-IGG3-E-Fc IgG3 VIT-301-IgG3 17.03 49.0^(∗) VP019TM-G4-A-DC V-TIM1-1 with V-IGG4-ADC-A-Fc IgG4 VIT-307 12.73 60.7^(∗)VP020 CT-G4-B-DC V-CTLD-1 with V-IGG4-ADC-B-Fc IgG4 VIT-308 19.18 91.9^(∗)multimer peak

The sequences of the expressed recombinant proteins are shown in table14.

TABLE 14 Sequences of expressed recombinant proteins. Protein NameDescription Sequence VP011 V-TIM1-1 with V-IGG1-FcSVKVGGEAGPSVTLPCHYSGAVTSMCWNRGSCSLFTCQNGIVWTNGTHVTYRKDTRYKLLGDLSRRDVSLTIENTAVSDSGVYCCRVEHRGWFNDMKITVSLEIVGGGGSGGGGSGGGGSDTPPPCPRCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFKWYVDGVEVHNAKTKPREEQYNSTFRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESSGQPENNYNTTPPMLDSDGSFFLYSKLTVDKSRWQQGNIFSCSVMHEALHNRFTQKSLSLSPGK (SEQ ID NO: 82) VP012 V-TIM1-1 withV-IGG3-D-Fc SVKVGGEAGPSVTLPCHYSGAVTSMCWNRGSCSLFTCQNGIVWTNGTHVTYRKDTRYKLLGDLSRRDVSLTIENTAVSDSGVYCCRVEHRGWFNDMKITVSLEIVGGGGSGGGGSGGGGSKTGDTTHTCPRCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFKWYVDGVEVHNAKTKPREEQYNSTFRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESSGQPENNYNTTPPMLDSDGSFFLYSRLTVDKSRWQQGNIFSCSVMHEALHNRFTQKSLSLSPGK (SEQ ID NO: 83) VP013 V-CTLD-1 withIgG1-Fc ERLCHPCPWEWTFFQGNCYFMSNSQRNWHDSITACKEVGAQLVVIKSAEEQNFLQLQSSRSNRFTWMGLSDLNQEGTWQWVDGSPLLPSFKQYWNRGEPNNVGEEDCAEFSGNGWNDDKCNLAKFWICKKSAASCSGGGGSGGGGSGGGGSDTPPPCPRCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFKWYVDGVEVHNAKTKPREEQYNSTFRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESSGQPENNYNTTPPMLDSDGSFFLYSKLTVDKSRWQQGNIFSCSVMHEALHNRFTQKSLSLSPGK (SEQ ID NO: 84) VP014 V-CTLD-1 withV-IGG3-E-Fc ERLCHPCPWEWTFFQGNCYFMSNSQRNWHDSITACKEVGAQLVVIKSAEEQNFLQLQSSRSNRFTWMGLSDLNQEGTWQWVDGSPLLPSFKQYWNRGEPNNVGEEDCAEFSGNGWNDDKCNLAKFWICKKSAASCSGGGGSGGGGSGGGGSKTGDTTHTCPRCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFKWYVDGVEVHNAKTKPREEQYNSTFRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESSGQPENNYNTTPPMLDSDGSFLLYSKLTVDKSRWQQGNIFSCSVMHEALHNRFTQKSLSLSPGK (SEQ ID NO: 85) VP015 V-TIM1-1 withV-IgG4-A-Fc SVKVGGEAGPSVTLPCHYSGAVTSMCWNRGSCSLFTCQNGIVWTNGTHVTYRKDTRYKLLGDLSRRDVSLTIENTAVSDSGVYCCRVEHRGWFNDMKITVSLEIVGGGGSGGGGSGGGGSKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 86) VP016 V-TIM1-1 withV-IgG4-A-Fc-CD3 (H3L3)SVKVGGEAGPSVTLPCHYSGAVTSMCWNRGSCSLFTCQNGIVWTNGTHVTYRKDTRYKLLGDLSRRDVSLTIENTAVSDSGVYCCRVEHRGWFNDMKITVSLEIVGGGGSGGGGSGGGGSKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGKGGGGSGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTRYTMHWVRQSPGQCLEWMGYINPSRGYTNYNQKFQGRVTMTTDKSTSTAYMELSSLRSEDTAVYYCARYYDDHYSLDYWGQGTTVTVSSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSElQLTQSPATLSLSPGERATLSCRASSSVSYMNWYQQKPGQAPRRWIYDTSKLATGIPARFSGSGSGTDYTLTISSLEPEDAAVYYCQQWSSNPFTFGC GTKLEIK (SEQ IDNO: 87) VP017 V-CTLD-1 with V-IgG4-B-FcERLCHPCPWEWTFFQGNCYFMSNSQRNWHDSITACKEVGAQLVVIKSAEEQNFLQLQSSRSNRFTWMGLSDLNQEGTWQWVDGSPLLPSFKQYWNRGEPNNVGEEDCAEFSGNGWNDDKCNLAKFWICKKSAASCSGGGGSGGGGSGGGGSKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFLLYSKLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 88) VP018 V-CTLD-1 withV-IgG4-B-Fc-CD3 (H3L3)ERLCHPCPWEWTFFQGNCYFMSNSQRNWHDSITACKEVGAQLVVIKSAEEQNFLQLQSSRSNRFTWMGLSDLNQEGTWQWVDGSPLLPSFKQYWNRGEPNNVGEEDCAEFSGNGWNDDKCNLAKFWICKKSAASCSGGGGSGGGGSGGGGSKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFLLYSKLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGKGGGGSGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTRYTMHWVRQSPGQCLEWMGYINPSRGYTNYNQKFQGRVTMTTDKSTSTAYMELSSLRSEDTAVYYCARYYDDHYSLDYWGQGTTVTVSSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSEIQLTQSPATLSLSPGERATLSCRASSSVSYMNWYQQKPGQAPRRWIYDTSKLATGIPARFSGSGSGTDYTLTISSLEPEDAAVYYCQQWSSNPFTFGC GTKLEIK (SEQ IDNO: 89) VP019 V-TIM1-1 with V-IGG4-ADC-A-FcSVKVGGEAGPSVTLPCHYSGAVTSMCWNRGSCSLFTCQNGIVWTNGTHVTYRKDTRYKLLGDLSRRDVSLTIENTAVSDSGVYCCRVEHRGWFNDMKITVSLEIVGGGGSGGGGSGGGGSKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKGLPSSIEKTISKCKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 90) VP020 V-CTLD-1 withV-IGG4-ADC-B-Fc ERLCHPCPWEWTFFQGNCYFMSNSQRNWHDSITACKEVGAQLVVIKSAEEQNFLQLQSSRSNRFTWMGLSDLNQEGTWQWVDGSPLLPSFKQYWNRGEPNNVGEEDCAEFSGNGWNDDKCNLAKFWICKKSAASCSGGGGSGGGGSGGGGSKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKGLPSSIEKTISKCKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFLLYSKLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 91) VP300 V-TIM1-1 and V-CTLD-1with V-IGG4-ADC-A-FcSVKVGGEAGPSVTLPCHYSGAVTSMCWNRGSCSLFTCQNGIVWTNGTHVTYRKDTRYKLLGDLSRRDVSLTIENTAVSDSGVYCCRVEHRGWFNDMKITVSLEIVGGGGSGGGGSGGGGSERLCHPCPWEWTFFQGNCYFMSNSQRNWHDSITACKEVGAQLVVIKSAEEQNFLQLQSSRSNRFTWMGLSDLNQEGTWQWVDGSPLLPSFKQYWNRGEPNNVGEEDCAEFSGNGWNDDKCNLAKFWICKKSAASCSGGGGSGGGGSGGGGSKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKGLPSSIEKTISKCKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 92) VP301 V-CTLD-1 andV-TIM1-1 with V-IGG4-ADC-A-FcERLCHPCPWEWTFFQGNCYFMSNSQRNWHDSITACKEVGAQLVVIKSAEEQNFLQLQSSRSNRFTWMGLSDLNQEGTWQWVDGSPLLPSFKQYWNRGEPNNVGEEDCAEFSGNGWNDDKCNLAKFWICKKSAASCSGGGGSGGGGSGGGGSSVKVGGEAGPSVTLPCHYSGAVTSMCWNRGSCSLFTCQNGIVWTNGTHVTYRKDTRYKLLGDLSRRDVSLTIENTAVSDSGVYCCRVEHRGWFNDMKITVSLEIVGGGGSGGGGSGGGGSKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKGLPSSIEKTISKCKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 93)

Example 9: Preparation of VP019 Fractions and VP025 Heterodimer

SEC-HPLC analysis of VP019 (FIG. 5 a ) shows that VP019 form theexpected homodimer (Fraction F6) and multimer ^(~)600 kDa (Fraction F2).The fractions were purified out and assessed separately for functionalactivity (VP019-F6 and VP019-F2, respectively named).

FIG. 5 b : SEC-HPLC analysis of VP020.

The protein product VP025, which is a heterodimer of VP019 and VP020,was generated by co-expressing Genes TM-G4-A-DC and CT-G4-B-DC inExpiCHO cells and purified by MabSelect SuRe protein A resin columnchromatography. The resulting co-transfected sample product was namedVP025-CT. FIG. 6 a shows that VP025-CT contains 4 distinct peaks whichwere purified out and assessed separately by intact mass spectrometry.The fractions from Peak 1 and Peak 2 showed a number of species.Fraction 3 from peak 3 (VP025-F3) showed a mass of 86,721 Da,corresponding to a VP020 homodimer (FIG. 6 b ). Fraction 4 from peak 4(VP025-F4) showed a mass of 83,881 Da, corresponding to the properlyformed VP019/VP020 heterodimer, at an approximate purity of 78% (FIG. 6c ).

Example 10: Expression and Purification of VP300 and VP301

Two additional bispecific molecules containing the TIM-1 and CTLDdomains on a single polypeptide chain (Table 15) were generated in 100mL ExpiCHO cells and purified by MabSelect SuRe protein A resin columnchromatography. The schematics and purity by SEC-HPLC are shown in FIGS.7 a and 7 b .

The sequences of the expressed recombinant proteins are shown in table14.

TABLE 15 Larger scale expression of protein constructs Protein Name GeneName Description Fc domain Yield (mg) VP300 TM-CT-G4-A-DC V-TIM1-1 andV-CTLD-1 with V-IGG4-ADC-A-Fc IgG4 2 VP301 CT-TM-G4-A-DC V-CTLD-1 andV-TIM1-1 with V-IGG4-ADC-A-Fc IgG4 2

Example 11: Binding of VP019, VP020 and VP025 to SARS-COV2 S Protein

The binding of VP019-F2, VP020 and VP025-CT to SARS-Cov-2 S D614G wasinvestigated by ELISA. This protein is representative of the dominantSARS-COV-2 strain in early 2020. All ELISA assays in this and subsequentexamples were done in the presence of 2.5 mM CaCl₂ since DC-SIGN isknown to use calcium at the binding site. Binding curves are shown inFIG. 8 and EC50 values are shown in Table 16. VP019-F2 had unexpectedlyhigh binding to SARS-COV2 S Protein, while VP020 had modest binding.

TABLE 16 EC50 for Binding of VP019, VP020 and VP025 to SARS-COV2 SProtein EC50 (mg/mL) EC50 (nM) VP019-F2 0.0009 10.6 VP020 0.0556 641.0VP025-CT 0.0069 82.5

Example 12: Binding of VP025-CT to Wide Range of Viral Antigens

The binding of VP025-CT to many diverse viral surface protein antigenswas investigated by ELISA. Binding curves are shown in FIG. 9 and EC50values are shown in Table 17.

TABLE 17 EC50 for binding of VP025-CT to several viral antigens EC50(mg/mL) EC50 (nM) West Nile Virus Envelope Protein 0.0049 57.9Chikungunya Virus E1 0.0102 121.5 Human RSV (A) Glycoprotein G 0.0696829.6 Influenza A H1N1 HA 0.0062 73.9 SARS-Cov-2 S D614G 0.0040 47.6Zika Virus Envelope Protein 0.0069 82.6 Dengue Virus 4 Envelope Protein0.0041 49.2 HIV-1 Clade C GP120 0.0055 65.9 EBOV Envelope Glycoprotein0.0106 126.1

Example 13: Binding of VP019, VP020, VP025-CT and VP025-F4 toPhosphatidyl Serine And viral antigens

The binding of VP019, VP020, VP025-CT (heterodimer mixture) and VP025-F4(78% pure heterodimer) to a biotin-phosphatidyl serine and a selectgroup of viral antigens (Influenza A H1N1 HA, Human RSV Glycoprotein G,Zika Virus Envelope Protein and SARS-Cov-2 S D614G) was investigated byELISA. Binding curves are shown in FIGS. 10 a and 10 b and EC50 valuesare shown in Table 18 and Table 19. VP025-F4 had stronger binding to allof the antigens than VP025-CT.

TABLE 18 EC50 in mg/mL for binding of VP019, VP020, VP025-CT andVP025-F4 to phosphatidyl serine and viral antigens VP019-F2 VP020VP025-CT VP025-F4 Biotin-PS 0.0098 0.0296 0.0056 0.0018 Influenza A H1N1HA 0.0021 0.0320 0.0034 0.0014 HRSV (A) Glycoprotein G 0.0073 0.00690.0043 0.0020 Zika Virus Envelope Protein 0.0010 0.0074 0.0020 0.0008SARS-Cov-2 S D614G 0.0017 0.0045 0.0012 0.0008

TABLE 19 EC50 in nM for binding of VP019, VP020, VP025-CT and VP025-F4to phosphatidyl serine and viral antigens VP019-F2 VP020 VP025-CTVP025-F4 Biotin-PS 121.1 340.7 66.6 21.9 Influenza A H1N1 HA 25.8 368.840.6 17.0 HRSV (A) Glycoprotein G 89.9 79.6 51.4 23.6 Zika VirusEnvelope Protein 12.2 85.1 24.0 10.0 SARS-Cov-2 S D614G 21.1 52.5 13.810.0

Example 14: Synthesis of Furin Inhibitor Linker-payloads

Solvents and reagents were purchased from Sigma-Aldrich, VWR, or FisherScientific, and used without further purification. Reactions weremonitored either by thin-layer chromatography (TLC) or by analyticalliquid chromatography-mass spectrometry (LC-MS) employing a WatersAcquity Ultra Performance LC system and a Synapt high-definition massspectrometer. ¹H NMR spectra were recorded on a Varian Unity INOVAspectrometer (500 MHz). All chemical shifts are reported in ppm andcoupling constants, J, are reported in hertz (Hz). NMR solvent peakswere referenced as follows: (¹H NMR) CDCl₃: 7.27 ppm, DMSO-d₆: 2.50 ppm.Compounds were purified by flash column chromatography on a TeledyneISCO Combi-Flash system using normal phase silica gel (SiliCycle Inc.)or reverse phase (Teledyne Gold- C18 or C18-Aq) pre-packed columns. Thepurity of compounds was determined by analytical HPLC (Waters AcquityUltra Performance) using an Acquity UPLC CSH C18 1.7 µm (50 mm x 2.1 mm)column and flow rate of 0.3 mL/min. Gradient conditions: solvent A(0.05% formic acid in water) and solvent B (0.05% formic acid inacetonitrile): 0-0.1 min 95% A, 0.1-4.0 min 5-95% B (linear gradient),4.0-5.0 min 95% B, UV detection at 254 nm and 220 nm.

The reaction scheme is shown in FIG. 12 .

N-methyl morpholine (13.8 µlL, 0.126 mmol) was added to a solution ofhexa-D-Arg (D-ArgininamideD-arginyl-D-arginyl-D-arginyl-D-arginyl-D-arginyl-D-alanine; Ambeed,cat# A333458) (30 mg, 0.0314 mmol), MC-Val-Cit-PAB-PNP (BroadPharm Cat#:BP-23292, CAS: 159857-81-5) (46.4 mg, 0.0629 mmol) and HOBt.H₂O(1-hydroxybenzotriazole monohydrate; 5.3 mg, 0.0345) in anhydrous DMF (1mL) under argon atmosphere. The solution was stirred at r.t. for 18hours. The reaction was diluted with 1:1 ACN/water (0.05% HCO₂H) (10 mL)and purified by reverse phase C18-Aq flash chromatography (gradientelution; 100% water -100% ACN with 0.05% HCO₂H as mobile phase additive)to afford MC-VC-PAB-(D-Arg)₆-NH₂ (12 mg, 0.00773 mmol, 25%) as a whitesolid after lyophilization. ¹H NMR (500 MHz, DMSO-d₆) d 10.09 (s, 1H),8.65 (br. s, 6H), 8.47 (s, 6H), 8.32 - 8.45 (m, 4H), 8.12 - 8.20 (m,1H), 7.84 (d, J = 7.8 Hz, 1H), 7.50 - 7.80 (m, 18H), 7.29 (d, J = 7.8Hz, 2H), 7.17 (s, 1H), 7.01 (s, 2H), 6.08 - 6.10 (m, 1H), 5.43 - 5.50(s, 2H), 4.89 - 5.01 (m, 2H), 4.36 - 4.41 (m, 1H), 4.12 - 4.30 (m, 6H),4.01 - 4.09 (m, 1H), 3.35 - 3.40 (m, 2H), 2.91- 3.12 (m, 12H), 2.09 -2.21 (m, 2H), 1.93 - 2.00 (m, 1H), 1.65 -1.75 (m, 6H), 1.40 -1.62 (m,28H), 1.30 -1.40 (m, 1H), 1.15 - 1.25 (m, 2H), 0.80 - 0.89 (m, 6H); MS(ESI) m/z: 1552.4 [M+H]⁺.

The structure is shown in FIG. 11 .

Example 15: Conjugation of Furin Inhibitor Payload to VP020

A test conjugation of Hexa-D-arginine linker-compound to VP020 wasperformed by reacting VP025 with 4 equivalents of TCEP and incubating at37° C. for 1 hour to reduce the free cysteines. The sample was runthrough a Zeba column to remove TCEP and buffer exchanged into 1x PBScontaining 1 mM DTPA pH 6.5. The sample was then reacted with 2.5equivalents of the payload (Mc-VC-PAB-(D-Arg6)-CONH2 at Room temperaturefor 1 hour. The final product was analyzed by mass spectrometry (seeFIG. 13 ) and shown to have the mass of 88,136 Da, near the expectedmass of 88,138 Da.

Example 16: RSV Neutralization Assay for VP019, VP020 and VP025

A microneutralization assay was done to determine the antiviralproperties of three compounds (VP019-F2, VP020 and VP025-F4) againstRSV. Each virus was incubated with each antibody for 1 hour, after whichthe mix was added to A549 cells (human lung cancer cell line). Antiviralactivity was determined 24 h later using an immunofluorescence-basedassay. After 24 h, the infection plates were washed with PBS, fixed for30 mins with 4% formaldehyde, washed again with PBS, and stored in PBSat 4° C. until staining. Any residual formaldehyde was quenched with 50mM ammonium chloride, after which cells were permeabilized (0.1% TritonX100) and stained with an antibody recognizing RSV fusion protein(GeneTex GTX40697). The primary antibody was detected with an Alexa-488conjugate secondary antibody (Life Technologies, A21244 and A11001), andnuclei were stained with Hoechst. Images were acquired on an CelllnsightCX5 high content platform (Thermo Scientific), and percentage infectioncalculated using CellInsight CX5 software (infected cells/total cells x100).

The test articles were used in concentrations of 0.5 µM and samples weretested in triplicate. The resulting data are shown in FIG. 14 . For RSV,VP019-F2 had 97% viral inhibition, compared to 55% inhibition forVP025-F5 and 28% inhibition for VP020.

Example 17: ZIKV Neutralization Assay for VP025

A second neutralization assay was done for Zika virus using VP025-F4using the following procedures.

Cell Culture Preparation

Vero E6 cells were maintained with DMEM supplemented with 2% FBS and (1%pen-strep -need to confirm with Allen) and stored at 37° C. with 5% CO₂.Cells were seeded onto 48-well plates at a concentration of 8.0*10⁴cells per well and allowed to adhere overnight. On the morning ofinfection cell monolayers were examined to ensure 90-95% confluency.

Test Zika Virus Neutralization

VP025-F4 was serially diluted in triplicate using infection media at aratio of 1:3 for a total of eight dilutions (220 to 0.1 µg/mL).). Zikavirus (ZIKV), strain MEX-I-44, at a MOI of 1.0 (8.0*10⁴ FFU) was addedto each dilution, mixed, and incubated at 37° C. and 5% CO₂ for onehour.

Positive Control Neutralization

Simultaneous to the VP025:ZIKV incubation, positive control samples werealso incubated. Mouse α-ZIKV MIAF (mouse immune ascitic fluid antibody)was diluted 1:500, 1:1000, and 1:1500 and combined with ZIKV, intriplicate, using the same concentration of virus as the test wells.

Plate Infection

Following incubation of VP025-F4:ZIKV and α-ZIKV MIAF:ZIKV, the Vero E6well plate was removed from the incubator. Media was aspirated from thecells and the test and positive control samples were transferred to theVero E6 plate and returned to the incubator to allow non-neutralizedvirus to infect cells for one hour.

Negative Control Focus Forming Assay

Simultaneous to the Plate Infection incubation, ZIKV was seriallydiluted (10⁻² to 10⁻⁵) and samples were allowed to infect Vero E6 cellsin triplicate.

Focus Reduction Neutralization Assay

Following the one hour incubation on Vero E6 cells an overlay of 0.8%methylcellulose was added to all wells and they were maintained at 37°C. and 5% CO₂ for approximately 60 hours.

Plates were removed from the incubator, overlay was aspirated, and cellswere gently washed twice with phosphate buffered saline. Virus wasinactivated with a 1:1 fixative mixture of methanol and acetone whichwas allowed to fix plates for 30 minutes. Following inactivation,fixative was removed, and plates were allowed to air dry until nofixative remained.

All incubations and washes were performed at room temperature and platewas placed on a plate rocker. Cells were permeabilized with 0.5% Tritonin PBS and washed with 0.02% Tween 20 in PBS (PBST). Blocking solutionof PBST with BSA and normal goat serum was prepared and incubated on allwells for one hour. Primary antibody, mouse α-ZIKV MIAF, was diluted inPBST with BSA and stored on ice until used. Blocking solution wasremoved and 1° antibody was incubated for one hour. Antibody was removedand plates were washed with PBST. Secondary antibody, goat α-mouse IgG(high and low chain) HRP conjugated, was diluted in PBST with BSA.Antibody was incubated on wells for one hour and then wells were washedwith PBST with BSA. Vector labs ImmPACT AMEC developing solution wasprepared according to kit instructions and added to each well. Plate wasincubated in the dark but checked regularly for staining. After fociwere clearly developed (^(~)15 minutes), wells were rinsed withdeionized water and the plate was allowed to dry.

Results

No foci were observed in the VP025-F4 test wells or the positive controlwells (see FIG. 14 b ). Foci developed as expected in the negativecontrol focus-forming assay wells demonstrating decreasing foci witheach successive virus dilution. This indicates that the VP025 testarticle was able to neutralize ZIKV at dilutions from (220 to 0.1µg/mL).

1. A fusion construct comprising an Ig-Fc domain or other proteinscaffold, such as albumin or an antibody fragment binding to albumin,and a. a peptide, protein or antibody fragment binding tophosphatidylserine and/or b. a peptide or protein binding to and/orrecognizing a PAMP expressed by a microbe.
 2. A fusion construct,preferably according to claim 1, comprising an IgG-Fc domain or otherprotein scaffold and a. a recombinant human TIM1 fragment and/or b. arecombinant human CD209 fragment.
 3. A fusion construct according to anyof claims 1-2, comprising an IgG-Fc domain or other protein scaffold,and a. A recombinant Ig-like V-type domain of a human TIM1 and/or b. Arecombinant C-type lectin domain of a human CD209 fragment.
 4. A fusionconstruct according to claim 3, comprising an IgG-Fc domain or otherprotein scaffold, and a. Two or more recombinant Ig-like V-type domainsfrom one or more human TIM1 and/or b. Two or more recombinant C-typelectin domains from one or more human CD209 fragment(s).
 5. A fusionconstruct comprising a. A recombinant Ig-like V-type domain of a humanTIM1 and b. A recombinant C-type lectin domain of a human CD209fragment.
 6. A fusion construct, preferably according to any of thepreceding claims comprising an IgG-Fc domain or other protein scaffoldand a. a recombinant human TIM1 fragment and/or b. a recombinant humanCD209 fragment and wherein said fusion construct provides enhanced ADCC,ADCP and/or CDC.
 7. A fusion construct, preferably according to any ofthe preceding claims comprising an IgG-Fc domain or other proteinscaffold and a. a recombinant human TIM1 fragment and/or b. arecombinant human CD209 fragment and wherein said fusion constructadditionally comprises the CDR regions according to SEQ ID No.: 54 - 59.8. A fusion construct, preferably according to any of the precedingclaims comprising an IgG-Fc domain or other protein scaffold and a. arecombinant human TIM1 fragment and/or b. a recombinant human CD209fragment and wherein said fusion construct further comprises a Furininhibitor.
 9. The fusion construct according to any of the precedingclaims, wherein said peptide, protein or antibody fragment is capable ofbinding to and/or stimulating an immune cell.
 10. The fusion constructaccording to any of the preceding claims, wherein said TIM1 fragment hasa sequence length selected from the group consisting of 40-200 aminoacid residues, 50-180 amino acid residues, 60-160 amino acid residues,70-140 amino acid residues, 80-130 amino acid residues, 90-120 aminoacid residues, 100-120 amino acid residues and 100-110 amino acidresidues.
 11. The fusion construct according to any of the precedingclaims, wherein said CD209 fragment has a sequence length selected fromthe group consisting of 40-200 amino acid residues, 40-190 amino acidresidues, 50-180 amino acid residues, 60-170 amino acid residues, 70-160amino acid residues, 80-150 amino acid residues, 90-150 amino acidresidues, 100-150 amino acid residues, 110-150 amino acid residues,120-150 amino acid residues and 130-140 amino acid residues.
 12. Thefusion construct according to any of the preceding claims, wherein saidTIM1 and/or CD209 fragment has a sequence homology of at least 70%,alternatively 75%, alternatively 80%, alternatively 85%, alternatively90%, alternatively 95% to wildtype TIM1 or CD209.
 13. The fusionconstruct according to any of the preceding claims, wherein said TIM1and/or CD209 fragment has intact TIM1 and/or CD209 function.
 14. Thefusion construct according to any of the preceding claims, wherein saidIgG-Fc domain is an IgG3-Fc domain.
 15. The fusion construct accordingto any of the preceding claims, comprising additionally at least one ofthe following: a) An IgG3, wherein the hinge sequence has been replaced,preferably with an IgG4 or IgG1 hinge sequence; b) CDR regions accordingto SEQ ID No.: 54 - 59; and/or c) A furin inhibitor.
 16. The fusionconstruct according to any of the preceding claims, wherein said fusionconstruct comprises a sequence according to SEQ ID No.: 1 and/or SEQ IDNo.: 2, or a sequence with at least 90% sequence identity, preferably atleast 95% sequence identity, more preferred at least 98% sequenceidentity to one of these sequences.
 17. The fusion construct accordingto any of the preceding claims, wherein said fusion construct comprisesa sequence according to SEQ ID No.: 3 and/or SEQ ID No.: 4, or asequence with at least 90% sequence identity, preferably at least 95%sequence identity, more preferred at least 98% sequence identity to oneof these sequences.
 18. The fusion construct according to any of thepreceding claims, wherein said fusion construct comprises at least 1, atleast 2, at least 3, at least 4, at least 5, at least 6, at least 7 orpreferably at least 8 disulfide bonds.
 19. The fusion constructaccording to any of the preceding claims, wherein said fusion constructis capable of binding to a target, and wherein said target is a mannan,a high-mannose containing structure, a fucan, a phospholipidphosphatidylserine and/or CD3.
 20. The fusion construct according to anyof the preceding claims, wherein said fusion construct comprises: a. Aprotein fragment comprising or consisting of a sequence according to SEQID No.: 1, or a sequence with at least 90% sequence identity, preferablyat least 95% sequence identity, more preferred at least 98% sequenceidentity to a sequence according to SEQ ID No.: 1, and b. a proteinfragment comprising or consisting of a sequence according to SEQ ID No.:3 or a sequence with at least 90% sequence identity, preferably at least95% sequence identity, more preferred at least 98% sequence identity toa sequence according to SEQ ID No.:
 3. 21. The fusion constructaccording to any of the preceding claims, wherein said fusion constructcomprises: a. A first chain comprising i. a sequence according to SEQ IDNo.: 1 or SEQ ID No.: 2, or a sequence with at least 90% sequenceidentity, preferably at least 95% sequence identity, more preferred atleast 98% sequence identity to one of these sequences and ii. a sequenceaccording to SEQ ID No.: 9 or a sequence according to SEQ ID No.: 43,,or a sequence with at least 90% sequence identity, preferably at least95% sequence identity, more preferred at least 98% sequence identity toone of these sequences and b. A second chain comprising iii. a sequenceaccording to SEQ ID No.: 1or SEQ ID No.: 2, or a sequence with at least90% sequence identity, preferably at least 95% sequence identity, morepreferred at least 98% sequence identity to one of these sequences, andiv. a sequence according to SEQ ID No.: 9 or a sequence according to SEQID No.: 43, or a sequence with at least 90% sequence identity,preferably at least 95% sequence identity, more preferred at least 98%sequence identity to one of these sequences.
 22. The fusion constructaccording to any of the preceding claims, wherein said fusion constructcomprises: a. A first chain comprising i. a sequence according to SEQ IDNo.: 3 or SEQ ID No.: 4, or a sequence with at least 90% sequenceidentity, preferably at least 95% sequence identity, more preferred atleast 98% sequence identity to one of these sequences, and ii. asequence according to SEQ ID No.: 9 or a sequence according to SEQ IDNo.: 43, or a sequence with at least 90% sequence identity, preferablyat least 95% sequence identity, more preferred at least 98% sequenceidentity to one of these sequences, and b. A second chain comprisingiii. a sequence according to SEQ ID SEQ ID No.: 3 or SEQ ID No.: 4, or asequence with at least 90% sequence identity, preferably at least 95%sequence identity, more preferred at least 98% sequence identity to oneof these sequences, and iv. a sequence according to SEQ ID No.: 9 or asequence according to SEQ ID No.: 43, or a sequence with at least 90%sequence identity, preferably at least 95% sequence identity, morepreferred at least 98% sequence identity to one of these sequences. 23.The fusion construct according to any of the preceding claims, whereinsaid fusion construct comprises: a. A first chain comprising i. asequence according to SEQ ID No.: 1 or SEQ ID No.: 2, or a sequence withat least 90% sequence identity, preferably at least 95% sequenceidentity, more preferred at least 98% sequence identity to one of thesesequences, and ii. a sequence according to SEQ ID No.: 11 or a sequenceaccording to SEQ ID No.: 45, or a sequence with at least 90% sequenceidentity, preferably at least 95% sequence identity, more preferred atleast 98% sequence identity to one of these sequences, and b. A secondchain comprising iii. a sequence according to SEQ ID No.: 3 or SEQ IDNo.: 4, or a sequence with at least 90% sequence identity, preferably atleast 95% sequence identity, more preferred at least 98% sequenceidentity to one of these sequences, and iv. a sequence according to SEQID No.: 13 or a sequence according to SEQ ID No.: 47, or a sequence withat least 90% sequence identity, preferably at least 95% sequenceidentity, more preferred at least 98% sequence identity to one of thesesequences.
 24. The fusion construct according to any of the precedingclaims, wherein said fusion construct comprises: a. A first chaincomprising i. a sequence according to SEQ ID No.: 1 or SEQ ID No.: 2, ora sequence with at least 90% sequence identity, preferably at least 95%sequence identity, more preferred at least 98% sequence identity to oneof these sequences, and ii. a sequence according to SEQ ID No.: 14 or15, or SEQ ID No.: 66, or a sequence with at least 90% sequenceidentity, preferably at least 95% sequence identity, more preferred atleast 98% sequence identity to one of these sequences, and b. A secondchain comprising iii. a sequence according to SEQ ID No.: 1 or SEQ IDNo.: 2, or a sequence with at least 90% sequence identity, preferably atleast 95% sequence identity, more preferred at least 98% sequenceidentity to one of these sequences, and iv. a sequence according to SEQID No.: 16 or 17, or SEQ ID No.: 67, or a sequence with at least 90%sequence identity, preferably at least 95% sequence identity, morepreferred at least 98% sequence identity to one of these sequences andv. a linker sequence, preferably according to SEQ ID No.: 41, and vi. asequence according to any of the sequences selected among SEQ ID No.:18 - 35, or a sequence with at least 90% sequence identity, preferablyat least 95% sequence identity, more preferred at least 98% sequenceidentity to one of these sequences.
 25. The fusion construct accordingto any of the preceding claims, wherein said fusion construct comprises:a. A first chain comprising i. a sequence according to SEQ ID No.: 3 orSEQ ID No.: 4, or a sequence with at least 90% sequence identity,preferably at least 95% sequence identity, more preferred at least 98%sequence identity to one of these sequences, and ii. a sequenceaccording to SEQ ID No.: 14 or 15, or SEQ ID No.: 66, or a sequence withat least 90% sequence identity, preferably at least 95% sequenceidentity, more preferred at least 98% sequence identity to one of thesesequences, and b. A second chain comprising iii. a sequence according toSEQ ID No.: 3 and/or SEQ ID No.: 4, or a sequence with at least 90%sequence identity, preferably at least 95% sequence identity, morepreferred at least 98% sequence identity to one of these sequences, andiv. a sequence according to SEQ ID No.: 16 or 17, or SEQ ID No.: 67, ora sequence with at least 90% sequence identity, preferably at least 95%sequence identity, more preferred at least 98% sequence identity to oneof these sequences and v. a linker sequence preferably according to SEQID No.: 41, and vi. a sequence according to any of the sequencesselected among SEQ ID No.: 18 - 35, or a sequence with at least 90%sequence identity, preferably at least 95% sequence identity, morepreferred at least 98% sequence identity to one of these sequences. 26.The fusion construct according to any of the preceding claims, whereinsaid fusion construct comprises: a. A first chain comprising i. asequence according to SEQ ID No.: 1 or SEQ ID No.: 2, or a sequence withat least 90% sequence identity, preferably at least 95% sequenceidentity, more preferred at least 98% sequence identity to one of thesesequences, and ii. a sequence according to SEQ ID No.: 14 or 15, or SEQID No.: 66, or a sequence with at least 90% sequence identity,preferably at least 95% sequence identity, more preferred at least 98%sequence identity to one of these sequences, and b. A second chaincomprising iii. a sequence according to SEQ ID No.: 3 or SEQ ID No.: 4,or a sequence with at least 90% sequence identity, preferably at least95% sequence identity, more preferred at least 98% sequence identity toone of these sequences, and iv. a sequence according to SEQ ID No.: 16or 17, or SEQ ID No.: 67, or a sequence with at least 90% sequenceidentity, preferably at least 95% sequence identity, more preferred atleast 98% sequence identity to one of these sequences, and v. a linkersequence preferably according to SEQ ID No.: 41, and vi. a sequenceaccording to any of the sequences selected among SEQ ID No.: 18 - 35, ora sequence with at least 90% sequence identity, preferably at least 95%sequence identity, more preferred at least 98% sequence identity to oneof these sequences.
 27. The fusion construct according to any of thepreceding claims, wherein said fusion construct comprises a. A firstchain comprising i. a sequence according to SEQ ID No.: 1 or SEQ ID No.:2, or a sequence with at least 90% sequence identity, preferably atleast 95% sequence identity, more preferred at least 98% sequenceidentity to one of these sequences, and ii. a sequence according to SEQID No.: 16 or 17, or SEQ ID No.: 67, or a sequence with at least 90%sequence identity, preferably at least 95% sequence identity, morepreferred at least 98% sequence identity to one of these sequences, andiii. a linker sequence preferably according to SEQ ID No.: 41, and iv. asequence according to any of the sequences selected among SEQ ID No.:18 - 35, or a sequence with at least 90% sequence identity, preferablyat least 95% sequence identity, more preferred at least 98% sequenceidentity to one of these sequences, and b. A second chain comprising v.a sequence according to SEQ ID No.: 3 or SEQ ID No.: 4, or a sequencewith at least 90% sequence identity, preferably at least 95% sequenceidentity, more preferred at least 98% sequence identity to one of thesesequences, vi. a linker sequence preferably according to SEQ ID No.: 41,and vii. a sequence according SEQ ID No.: 14 or 15, or SEQ ID No.: 66,or a sequence with at least 90% sequence identity, preferably at least95% sequence identity, more preferred at least 98% sequence identity toone of these sequences.
 28. The fusion construct according to any of thepreceding claims, wherein said fusion construct comprises a linker. 29.The fusion construct according to any of the preceding claims, whereinsaid linker is selected among a (GGGGS)3 linker (SEQ ID NO. 41), a(GGGGS)4 linker (SEQ ID NO. 70), a (GGGGS)5 linker (SEQ ID NO. 71) and a(GGGGS)6 linker (SEQ ID NO. 72).
 30. The fusion construct according toany of the preceding claims, wherein said fusion construct comprises atleast one free cysteine residue, at least two free cysteine residues, atleast three free cysteine residues, at least four free cysteineresidues, at least five free cysteine residues or preferably at leastsix free cysteine residues.
 31. The fusion construct according to any ofthe preceding claims, wherein said free cysteine allows interaction witha drug and/or a payload.
 32. The fusion construct according to any ofthe preceding claims, wherein said payload is a furin inhibitor.
 33. Thefusion construct according to any of the preceding claims, wherein saidfusion construct comprises a A339C mutation, a S337C mutation and/or aK340C mutation.
 34. The fusion construct according to any of thepreceding claims, wherein said fusion construct comprises a sequenceselected among any of the sequences SEQ ID No.: 36, 37, SEQ ID No.: 38,39, 40, 42, 44 or
 46. 35. The fusion construct according to any of thepreceding claims, wherein said fusion construct is an IgG1, IgG2, IgG3or an IgG4.
 36. The fusion construct according to any of the precedingclaims, wherein said fusion construct is an IgG, IgM, IgA, IgD or anIgE.
 37. The fusion construct according to any of the preceding claims,wherein said fusion construct comprises a null fc.
 38. The fusionconstruct according to any of the preceding claims, wherein said null fccomprises an Ala substitution at position 234 and/or Ala substitution at235, and/or N297A, and/or a K322A mutation.
 39. The fusion constructaccording to any of the preceding claims, wherein said fusion constructcomprises a heterodimerization domain.
 40. The fusion constructaccording to any of the preceding claims, wherein saidheterodimerization domain comprises a sequence according to SEQ ID No.:48, 49 or
 50. 41. The fusion construct according to any of the precedingclaims, wherein said fusion construct comprises a heterodimerizationmutation.
 42. The fusion construct according to any of the precedingclaims, wherein said heterodimerization mutation is an F405L, R409Kand/or K409R mutation.
 43. The fusion construct according to any of thepreceding claims, wherein said fusion construct comprises: a. A firstchain comprising i. a sequence according to SEQ ID No.: 1 or SEQ ID No.:2, or a sequence with at least 90% sequence identity, preferably atleast 95% sequence identity, more preferred at least 98% sequenceidentity to one of these sequences, and ii. a sequence according to SEQID No.: 38, or a sequence with at least 90% sequence identity,preferably at least 95% sequence identity, more preferred at least 98%sequence identity to this sequence, and b. A second chain comprisingiii. a sequence according to SEQ ID No.: 1 or SEQ ID No.: 2, or asequence with at least 90% sequence identity, preferably at least 95%sequence identity, more preferred at least 98% sequence identity to oneof these sequences, and iv. a sequence according to SEQ ID No.: 38, or asequence with at least 90% sequence identity, preferably at least 95%sequence identity, more preferred at least 98% sequence identity to thissequence.
 44. The fusion construct according to any of the precedingclaims, wherein said fusion construct comprises: a. A first chaincomprising i. a sequence according to SEQ ID No.: 3 or SEQ ID No.: 4, ora sequence with at least 90% sequence identity, preferably at least 95%sequence identity, more preferred at least 98% sequence identity to oneof these sequences, and ii. a sequence according to SEQ ID No.: 38, or asequence with at least 90% sequence identity, preferably at least 95%sequence identity, more preferred at least 98% sequence identity to oneof these sequences, and b. A second chain comprising iii. a sequenceaccording to SEQ ID No.: 3 or SEQ ID No.: 4, or a sequence with at least90% sequence identity, preferably at least 95% sequence identity, morepreferred at least 98% sequence identity to one of these sequences, andiv. a sequence according to SEQ ID No.: 38, or a sequence with at least90% sequence identity, preferably at least 95% sequence identity, morepreferred at least 98% sequence identity to one of these sequences. 45.The fusion construct according to any of the preceding claims, whereinsaid fusion construct comprises: a. A first chain comprising i. asequence according to SEQ ID No.: 1 or SEQ ID No.: 2, or a sequence withat least 90% sequence identity, preferably at least 95% sequenceidentity, more preferred at least 98% sequence identity to one of thesesequences, and ii. a sequence according to SEQ ID No.: 38, or a sequencewith at least 90% sequence identity, preferably at least 95% sequenceidentity, more preferred at least 98% sequence identity to one of thesesequences, and b. A second chain comprising iii. a sequence according toSEQ ID No.: 3 or SEQ ID No.: 4, or a sequence with at least 90% sequenceidentity, preferably at least 95% sequence identity, more preferred atleast 98% sequence identity to one of these sequences, and iv. asequence according to SEQ ID No.: 40, or a sequence with at least 90%sequence identity, preferably at least 95% sequence identity, morepreferred at least 98% sequence identity to one of these sequences. 46.The fusion construct according to any of the preceding claims, whereinsaid fusion construct comprises: a. A first chain comprising i. asequence according to SEQ ID No.: 1 or SEQ ID No.: 2, or a sequence withat least 90% sequence identity, preferably at least 95% sequenceidentity, more preferred at least 98% sequence identity to one of thesesequences, and ii. a linker sequence according to SEQ ID No.: 41, andiii. a sequence according to SEQ ID No.: 65, or a sequence with at least90% sequence identity, preferably at least 95% sequence identity, morepreferred at least 98% sequence identity to one of these sequences b. Asecond chain comprising iv. a sequence according to SEQ ID No.: 1 or SEQID No.: 2, or a sequence with at least 90% sequence identity, preferablyat least 95% sequence identity, more preferred at least 98% sequenceidentity to one of these sequences, and v. a linker sequence accordingto SEQ ID No.: 41, and vi. a sequence according to SEQ ID No.: 65, or asequence with at least 90% sequence identity, preferably at least 95%sequence identity, more preferred at least 98% sequence identity to oneof these sequences.
 47. The fusion construct according to any of thepreceding claims, wherein said fusion construct comprises: a. A firstchain comprising i. a sequence according to SEQ ID No.: 3 or SEQ IDNo.:4, or a sequence with at least 90% sequence identity, preferably atleast 95% sequence identity, more preferred at least 98% sequenceidentity to one of these sequences, and ii. a linker sequence accordingto SEQ ID No.: 41, and iii. a sequence according to SEQ ID No.: 65, or asequence with at least 90% sequence identity, preferably at least 95%sequence identity, more preferred at least 98% sequence identity to oneof these sequences b. A second chain comprising iv. a sequence accordingto SEQ ID No.: 3 or SEQ ID No.: 4, or a sequence with at least 90%sequence identity, preferably at least 95% sequence identity, morepreferred at least 98% sequence identity to one of these sequences, andv. a linker sequence according to SEQ ID No.: 41, and vi. a sequenceaccording to SEQ ID No.: 65, or a sequence with at least 90% sequenceidentity, preferably at least 95% sequence identity, more preferred atleast 98% sequence identity to one of these sequences.
 48. The fusionconstruct according to any of the preceding claims, wherein said fusionconstruct comprises: a. A first chain comprising i. a sequence accordingto SEQ ID No.: 1 or SEQ ID No.: 2, or a sequence with at least 90%sequence identity, preferably at least 95% sequence identity, morepreferred at least 98% sequence identity to one of these sequences, andii. a linker sequence according to SEQ ID No.: 41, and iii. a sequenceaccording to SEQ ID No.: 65, wherein said sequence ID No.: 65 comprisesone or more of the mutations of table 8 b. A second chain comprising iv.a sequence according to SEQ ID No.: 3 or SEQ ID No.: 4, or a sequencewith at least 90% sequence identity, preferably at least 95% sequenceidentity, more preferred at least 98% sequence identity to one of thesesequences, and v. a linker sequence according to SEQ ID No.: 41, and vi.a sequence according to SEQ ID No.: 65, wherein said sequence ID No.: 65comprises one or more of the mutations of table
 8. 49. The fusionconstruct according to any of the preceding claims, wherein the ratio offusion construct to said drug and/or payload is selected among 1, 2, 3,4, 5, 6, 7, 8, 9 or
 10. 50. The fusion construct according to any of thepreceding claims, wherein said fusion construct comprises a kappa lightchain according to SEQ ID No.: 51 or a lambda light chain according toSEQ ID No.: 52 or
 53. 51. A fusion construct, preferably according toany of the preceding claims, wherein said fusion construct is an IgG3construct, and wherein said IgG3 construct comprises a hinge region,wherein said hinge region has been modified.
 52. The fusion constructaccording to claim 51, wherein said hinge region comprises a sequencehaving a total of at least 10% identity, at least 15%, at least 20%, atleast 25%, at least 30%, at least 35%, at least 40%, at least 45%, atleast 50%, at least 55%, at least 60%, at least 65%, at least 70%, atleast 75%, at least 80%, at least 85%, at least 90%, at least 95% or atleast 99% identity to the sequence according to SEQ ID No.: 6 or SEQ IDNo.:
 8. 53. The fusion construct according to any of the precedingclaims, wherein said fusion construct comprises the sequence accordingto SEQ ID No.: 5, 7, 9, 10, 11, 12 and/or
 13. 54. The fusion constructaccording to any of the preceding claims, wherein said hinge regioncomprises at least one free cysteine residue, at least two free cysteineresidues or preferably at least three free cysteine residues.
 55. Thefusion construct according to any of the preceding claims, wherein saidhinge region comprises a S228P mutation.
 56. The fusion constructaccording to any of the preceding claims, wherein said hinge regioncomprises a sequence according to SEQ ID No.: 6 and/or SEQ ID No.: 8and/or SEQ ID No.:
 68. 57. The fusion construct according to any of thepreceding claims, wherein said fusion construct is used to detectphosphatidylserine.
 58. The fusion construct according to any of thepreceding claims, wherein said fusion construct is used to detectphosphatidylserine in the blood of a subject.
 59. The fusion constructaccording to claim 57, wherein said fusion construct comprises asequence according to SEQ ID No.: 1, and/or a sequence according to SEQID No.:
 2. 60. The fusion construct according to any of the precedingclaims, wherein said fusion construct is used to detect C-type lectinbinding mannan or fucan moieties.
 61. The fusion construct according toany of the preceding claims, wherein said fusion construct is used todetect C-type lectin binding mannan or fucan moieties in the blood of asubject.
 62. The fusion construct according to claim 60, wherein saidfusion construct comprises a sequence according to SEQ ID No.: 3 and/ora sequence according to SEQ ID No.:
 4. 63. A fusion construct, a fusionprotein or an antibody comprising the constant region(s) of IgG3 and ahinge, wherein said hinge preferably is selected among an IgG1 or IgG4hinge.
 64. The fusion construct, fusion protein or antibody according toany claim 63, comprising one or more heterodimerization mutations. 65.The fusion construct, fusion protein or antibody according to claim 64,comprising heterodimerization mutations involving or including positions405 and/or 409 (EU numbering).
 66. IgG3 homodimer comprising a hingeregion, wherein said hinge region comprises a sequence selected amongSEQ ID No.: 6, 8 and
 68. 67. IgG3 heterodimer comprising a hinge region,wherein said hinge region comprises a sequence selected among SEQ IDNo.: 6, 8 and
 68. 68. IgG3 according to any of claims 66-67, whereinsaid IgG3 comprises a mutation at position 405 and/or position
 409. 69.IgM heterodimers obtainable by changing the charge pairs of the CH2and/or CH4 domains.
 70. IgM heterodimers according to claim 69,comprising one or more of the mutations of Table
 8. 71. The IgMaccording to any claims 69-70, wherein said IgM comprises a sequenceaccording to SEQ ID No.: 64 and/or
 65. 72. A fusion construct accordingto any of claims 1-65, wherein said fusion construct comprises an IgG3homodimer, an IgG3 heterodimer and/or an IgM heterodimer according toany of claims 66-71.
 73. The fusion construct according to any of thepreceding claims, wherein said fusion construct is for use in thetreatment of an infection.
 74. The fusion construct according to claim73, wherein said infection is an infection caused by a virus, such asCoronaviruses SARS-COV, a parasite, a bacteria, a fungi or a protozoan.75. The fusion construct according to claims 74, wherein said virus isselected among an arborvirus, Zika virus, Dengue virus, West Nile virus,Ebola virus, influenza virus, influenza virus H1N1, Chikungunya virus,enterovirus, Coronavirus SARS-COV-2 and Coronaviruses SARS-COV.
 76. Thefusion construct according to claim 74, wherein said bacteria isselected among mycobacterium tuberculosis and mycobacterium leprae. 77.The fusion construct according to claim 74, wherein said parasite isselected among Leishmaniasis and Malaria.
 78. Use of a fusion constructaccording to any of claims 1-71, for the treatment of an infection. 79.Use according to claim 78, wherein said infections are selected amongviral, bacterial and protozoan infections.
 80. Use according to anyclaims 78-79, wherein the treatment comprising administration of thefusion construct with an administration form selected amongsubcutaneous, intradermal, intramuscular, oral and nasal.
 81. Use ofIgG4 or a part of IgG4 for payload delivery, wherein said IgG4 has beenmodified to comprise no Fc or wherein the activity of the Fc of saidIgG4 has been nullified or diminished by one or more mutations.
 82. Theuse according to any of claims 78-81, wherein said IgG4 comprises one ormore heterodimerization mutations.
 83. The use according to any ofclaims 81-82, wherein said IgG4 comprises one or more Cys mutations,preferably thereby allowing site specific conjugation.
 84. The useaccording to any of claims 81-83, wherein said IgG4 comprises a Cys atposition 339 (EU numbering).
 85. A vaccine comprising a fusion constructaccording to any of claims 1-65.
 86. A vaccine comprising a mannan, ahigh mannose containing structure, a fucan and/or a phospholipidphosphatidylserine (PS).
 87. The vaccine according to claim 85 or 86,further comprising β-glucan.
 88. The vaccine according to any of claims85-87, for the prevention and/or treatment of an infection.
 89. Thevaccine according to claim 88, wherein said infection is caused by avirus, preferably according to claim 75, and/or Coronaviruses SARS-COV,a parasite, preferably according to claim 77, a bacteria, preferablyaccording to claim 76, a fungi or a protozoan.
 90. The fusion constructaccording to any of claims 1-65 and/or vaccine according to any ofclaims 85-89, wherein said fusion construct and/or vaccine allowsadministration through a route selected among subcutaneousadministration, intradermal administration, intramuscularadministration, oral administration and/or nasal administration.
 91. Acomposition comprising a fusion construct according to any of claims1-65, optionally comprising one or more excipients such as diluents,binders or carriers.
 92. A method of treating and/or preventing aninfection in a subject, comprising a step of administration of a fusionconstruct according to any of claims 1-65 and/or a vaccine according toany of claims 85-89 and/or a composition according to any of claims90-91.
 93. A method of screening and/or monitoring progression of adisease in a subject, wherein said method comprises the following steps:i. Providing a blood sample from said subject. ii. Contacting said bloodsample with a fusion construct according to any of claims 1-65.
 94. Anisolated nucleic acid molecule encoding a fusion construct according toany of claims 1-65.
 95. A recombinant vector comprising the nucleic acidmolecule of claim
 94. 96. A host cell comprising the recombinant vectorof claim
 95. 97. A method for the production of a fusion constructaccording to any of the precedent claims comprising a step of culturingthe host cell according to claim 96 in a culture medium under conditionsallowing the expression of the fusion construct and separating thefusion construct from the culture medium.